Travis

Member
Joined
Jul 14, 2016
Messages
3,189
Pellagra is fairly well understood, but there is still some persistent mythology surrounding the etiology. Everyone knows that niacin is the characteristic deficiency, but few are aware of the central importance that leucine plays in this. The somewhat low tryptophan and niacin content of corn is stressed, with little attention given to the main causative agent—if any.

Sorgham causes pellagra, yet has a fair amount of tryptophan and and free niacin. The most salient commonality between sorgham and corn is their extraordinarily high leucine concentrations, as expressed as the ratio to total protein.

'A comparison of the chemical composition of rice, jowar, and maize shows that the nicotinic acid content of jowar is nearly similar to that of rice. The tryptophan content of jowar varies widely, certain strains having nearly as high a content of tryptophan as rice, while certain others have somewhat lower values. Both jowar and maize have, however, one common feature with regard to their amino acid composition: a high content of leucine.' ―Gopalan

pellagra.png click to embiggen

'Experimental pellagra was produced in six adult monkeys by feeding diets containing jowar. Clinical and pathological features of this syndrome were indistinguishable from those seen in a group which developed the deficiency on maize diet.' ―Gopalan

What is unique about leucine is its ability to increase the elimination of nicotinic acid (B₃). In a study on adult males over fifty years ago, Gopalan showed the extent of this effect (using only five grams of leucine):

'The rise in N.M.N. [N‐methyl nicotinic acid] excretion brought about by 5 grams L‐leucine daily represented an increase of nearly 50% over the basal level.'―Gopalan

pellagra2.pngclick to embiggen

'The increase in N.M.N. excretion brought about by supplementation with 5 grams of L‐leucine daily would roughly correspond to the metabolism of an additional 3–5 milligram nicotinic acid daily.' ―Gopalan

This is a common observation, seen in animals of all types. Isoleucine or valine doesn't do this; this effect is particular to leucine.

Gopalan, C. "Leucine and pellagra." The Lancet (1960)
Gopalan, C. "Leucine and pellagra." Nutrition reviews (1968)

Nixtamalization is process where the corn is ground, mixed with water, mixed with alkali, and then strained. This represents a separation procedure, and is known to ameliorate the pellagric effect of corn. The change in amino acid composition has been studied, with significant reductions in the leucine content observed.

'From these figures the average amino acid changes were then calculated. There was a 21.0% decrease for leucine, 18.7% for arginine, 12.5%, for cystine, 11.7% for histidine, and 5.3% for lysine. Of the nonessential amino acids, changes were found in proline, serine, and glutamic acid, amounting respectively to a decrease of 8.7, 7.1, and 6.3%.' —Bressani

pellagra3.png click to embiggen

'On the other hand, an average of 21% of leucine was lost in the process, a change which should improve the biological value of tortilla protein by partially correcting the isoleucine to leucine disproportion.' —Bressani

This is best explained by the fact that the increased pH causes a precipitation of the protein zein, the alcohol‐soluble fraction. This is then discarded with the water, along with much of the leucine content. Nixtamalization represents a balancing of the amino acid profile. The idea that this process serves to 'liberate niacin' is naïve, considering the fact that sorghum—and even leucine itself—has been shown to cause pellagra. Reading mythological narratives about 'bound niacin' leaves the reader befuddled; it is never explained what it's bound to. Accepting this is akin to accepting the notion that corn has a peculiar and ill‐defined ability to bind niacin, an effect reversed by alkalinity in vitro but not by alkalinity in vivo (duodenal). Moreover, the mythological resilient niacin–protein bond is necessarily unaffected by the hydrochloric acid, the pepsin, the trypsin, and the twelve hours of bacterial action in the digestive tract.


Kodicek, E. "The availability to pigs of nicotinic acid in tortilla baked from maize treated with lime-water." British Journal of Nutrition (1959)
Bressani, Ricardo. "Lime-heat effects on corn nutrients, effect of lime treatment on in vitro availability of essential amino acids and solubility of protein fractions in corn." Journal of Agricultural and Food chemistry (1958)

Why exactly would leucine—of all things—increase the elimination of niacin? So far, I have yet to see an acceptable answer for this. All the articles I've read on this topic leave the question open; there has been little attempt to explain why this should be. Naturally, there are those who think responses like this happen by accident; the explanation that 'leucine inhibits quinolinate phosphoribosyl transferase' (wikipedia.org) is an acceptable explanation for those people.

'Nature does not indulge in luxuries and if there is such a widely spread and highly active enzyme, it must have something very important to do...' ―Albert Szent‐Györgyi

But this explanation fails, for example, to explain why leucine increases tryptophan oxygenase activity; the entire kyneurenine pathway is increased, and shifted. Relatively small changes in leucine divert the kyneurenine pathway from the niacin arm to the picolinate arm:

'To understand the biochemical basis of leucineinduced changes in tryptophan-niacin metabolites, the effects of dietary leucine on the enzymes involved in tryptophan-niacin metabolism were investigated. The enzymes studied were tryptophan oxygenase, 3-hydroxyanthranilate oxygenase, picolinate carboxylase, quinolinate phosphoribosyltransferase and nicotinate phosphoribosyltransferase.' ―Narasinga

pellagra4.png pellagra5.png click to embiggen

'A decreased activity of quinolinate phosphoribosyltransferase may also partly explain the increased quinolinic acid excretion observed in the presence of excess of leucine in the diet (Raghuramulu et al., 1965a; Belavady et al., 1963). The fact that leucine in the presence of added niacin decreased the enzyme activity without affecting quinolinic acid excretion (Raghuramulu et al., 1965a) suggests other mechanisms contributing to increased quinolinic acid excretion.' ―Narasinga

The data does not suggest a simple inhibition of one enzyme; the data suggests a purposeful adaption to excessive leucine, forming picolinate at the expense of niacin.

Excessive amino acids are generally decarboxylated first, then perhaps deanimated. First glance at leucine gives hints about what it could be used for: Leucine's carbon skeleton—sans carbon dioxide—is essentially a saturated isoprene, inviting the speculation that it could be used in cholesterol synthesis. This speculation turns out to be correct, and ¹⁴C‐leucine has been shown to be incorporated into sterols in three Leishmania species—and even in rats:

'The results presented here demonstrate that leucine acts as a major precursor to sterols in several Leishmania species and also in the closely related organism E. monterogeii. Some Leishmania species derived considerably more of their sterol from a leucine source of carbon than did others (Table 3) but there was no apparent correlation between the extent of leucine utilization for sterol production and the origin of the organism as an Old World or New World species.' ―Ginger

leucine.png click to embiggen

'The conversion of leucine to cholesterol in muscle tissue was about 200 times that of acetate and about 25 times that of mevalonate. Utilisation of leucine for cholesterol synthesis was greater than that of acetate and of mevalonate even in intestine and kidney, whereas in liver homogenate acetate and mevalonate were better precursors than leucine.' ―Miettinen

In both protazoa and mammals, leucine can serve as a substrate for steroid synthesis—a fact of central importance to lecucine‐induced pellagra.

Szent-Györgyi, Albert. "The living state and cancer." Proceedings of the National Academy of Sciences (1977)
Rao, BS Narasinga. "Effect of leucine on enzymes of the tryptophan–niacin metabolic pathway in rat liver and kidney." Biochemical Journal (1973)
Ginger, Michael L. "The biosynthetic incorporation of the intact leucine skeleton into sterol by the trypanosomatid Leishmania mexicana." Journal of Biological Chemistry (2001)
Miettinen, T. A. "Comparison of leucine with mevalonate and acetate as a precursor of tissue and serum cholesterol in the rat." Annales medicinae experimentalis et biologiae Fenniae (1971)
Ginger, Michael L. "Utilization of leucine and acetate as carbon sources for sterol and fatty acid biosynthesis by Old and New World Leishmania species, Endotrypanum monterogeii and Trypanosoma cruzi." The FEBS Journal (2000)

Picolinate is no stranger to biology, and perhaps its most particular feature is its ability to chelate zinc. Even commercially, zinc is commonly sold as a picolinate chelate. This is a high‐affinity bond which has biological importance. Picolinate supplementation increases the absorption of dietary zinc, and it wouldn't be a stretch to imagine endogenous picolinate increases the absorption of zinc. This turns out to be true, as was proven by G.W. Evans:

'Those investigators noted that the metabolism of tryptophan was impaired in children who were affected with acrodermatitis enteropathica and suggested that the genetic defect in this disease involved an enzyme in the pathway from tryptophan to nicotinic acid. We believed that this malady resulted from an impaired production of an essential zinc-binding ligand. We thus investigated the possibility that a tryptophan metabolite might be the long sought after zinc binding ligand.' ―Evans

'Rats fed a zein-based diet (20 percent protein) supplemented with lysine but not with tryptophan absorbed only 59 percent of the daily dietary zinc intake. Rats fed the zein diet supplemented with both lysine and tryptophan absorbed 98 percent of the dietary zinc intake, and rats fed the zein diet supplemented with lysine and picolinic acid absorbed 75 percent of the dietary zinc intake (Table 1).' ―Evans

zinc2.png zinc.png click to embiggen

'These observations establish the fact that zinc absorption is affected by levels of both dietary tryptophan and pyridoxine. Furthermore, the results demonstrate that supplemental picolinic acid ameliorates the impaired zinc absorption caused by a deficiency of either tryptophan or pyridoxine. Because picolinic acid is a metabolic product of tryptophan and depends upon pyridoxine for its production, these results provide strong evidence that endogenous picolinic acid is essential for normal zinc absorption.' ―Evans

'The studies reviewed suggest that zinc absorption proceeds as follows: in the exocrine cells of the pancreas the metabolism of tryptophan produces picolinic acid which is secreted into the lumen of the intestine. In the lumen, picolinic acid coordinates with Zn²⁺ to form a complex which facilitates the passage of Zn²⁺ through the luminal membrane, across the absorptive cell and through the basolateral membrane of the cell.' ―Evans

This is another fact to keep in mind—a necessary step in explaining why the body does what it has been shown to do, in response to excess leucine.

Evans, G. W. "Normal and abnormal zinc absorption in man and animals: the tryptophan connection." Nutrition reviews (1980)
Seal, Christopher J. "Effect of dietary picolinic acid on the metabolism of exogenous and endogenous zinc in the rat." The Journal of nutrition (1985)

Zinc increases cholesterol biosynthesis. This is another consistent finding, which is observed in humans with zinc supplementation.

'On day 43, there was a significant elevation in the serum total cholesterol for subjects in the zinc-supplemented group (191.44 mg/dL) compared with the control group (151.42 mg/dL). No significant changes were noted in the serum total cholesterol in the control group from day 0 (146.61 mg/dL) to day 43 (151.42 mg/dL).' ―Roozbeh

This is also observed in rats, and the inclusion of zinc to their diet predictable lead to hypercholesterolemia.


'However, several studies have shown a role for zinc in determining serum cholesterol and triglyceride levels: a zinc-deficient diet induces hypotriglyceridemia in rats and hypocholesterolemia in rats and pigs; zinc supplemented swines had higher cholesterol levels than their unsupplemented counterparts during the first 4 weeks of treatment; Lei using a moderately copper-deficient diet supplemented with zinc obtained a hypercholesterolemia in the rat.' ―Katya-Katya

zinc3.png click to embiggen

'At the end of the experiment, the zinc-supplemented rats had a 50% higher cholesterol concentration than the control rats.' ―Katya-Katya

The regulatory cascade which orchestrates cholesterol synthesis is zinc‐dependent. The enzyme required in the second canonical stage needs zinc ions to function, a fact which can explain how dietary zinc can effect cholesterol levels so powerfully.

'Site-2-protease (S2P), a member of the family of zinc metalloproteases, catalyzes hydrolysis of the second proteolytic reaction on SREBP [sterol regulatory element binding protein], which releases a soluble transcription factor (the amino-terminal fragment of SREBP). The soluble transcription factor enters the nucleus, where it binds to direct repeat sterol response elements in promotor regions, activating transcription of sterol-regulated cholesterogenic genes. Genes under this regulatory control include, at least, LDL receptor, HMG-CoA synthase, HMG-CoA reductase, farnesyl diphosphate synthase, squalene synthase, lanosterol synthase, and lanosterol 14α-methyl demethylase cytochrome P450. Activation of these genes restores intracellular cholesterol levels.' ―Risley

''The first RIP system to be molecularly characterized was the cleavage of the membrane-anchored transcription factor SREBP (sterol regulatory element–binding protein) by a metalloprotease known as site-2 protease (S2P). This cleavage releases a transcription factor, which translocates into the nucleus of the cell and activates genes involved in synthesis and uptake of cholesterol and fatty acids.' ―Feng

Besides site‐2‐protease, other zinc metalloproteases are involved in lipid synthesis. A study conducted in 1998 shows the zinc dependency of sphingomyelinase directly.

'We then tested this purified L-SMase for zinc dependence and found that its enzymatic activity was increased 4.7-fold in the presence of Zn²⁺.' ―Schissel

zinc4.png click to embiggen

'the data in this report strongly support the conclusion that this enzyme is, indeed, a zinc‐activated enzyme.' ―Schissel

The enzyme responsible for the second, and indispensible, step in canonical cholesterol regulation has been characterized. It has been found to contain a considerable amount of zinc, bound tightly, coordinated by histidine (of course):

'S2P has six transmembrane segments, TM1 through TM6. The catalytic zinc atom is located ~14 Å from the lipid membrane surface. Zinc is coordinated by three amino acids, His⁵⁴ and His⁵⁸ in TM2, and Asp¹⁴⁸ in TM3, which are highly conserved in all S2P proteins.' ―Feng

'As previously hypothesized, the catalytic zinc atom is coordinated by three amino acids that are invariant among all S2P family proteins: His⁵⁴ and His⁵⁸ from helix a2 and Asp¹⁴⁸ from the N‐terminal end of helix [...]. The zinc atom is located ~14 Å below the lipid membrane surface from the cytosolic side.' ―Feng

'Quantitative element analysis by inductively coupled plasma emission spectrometry revealed that, compared with the WT protein, the zinc content was 8.2, 44.2, 5.1, and 15.1% for the mutant proteins H54A, E55A, H58A, and D148A, respectively.' ―Feng

Radioactive ¹⁴C‐leucine has been shown to be incorporated into the cholesterol skeleton by mammals, including mice; picolinate has been shown to chelate zinc, and so has tryptophan (ostensibly via picolinate); zinc has unambiguously been shown to increase cholesterol synthesis; what follows from this is an explanation why dietary leucine increases the production of picolinate at the expense of niacin: It purposefully does so as a device to increase the absorption of the obligatory dietary zinc for cholesterol synthesis, the most efficient way for the body to deal with excessive leucine.

Risley, John M. "Cholesterol biosynthesis: Lanosterol to cholesterol." J. Chem. Educ (2002)
Feng, Liang. "Structure of a site-2 protease family intramembrane metalloprotease." Science (2007)
Katya-Katya, M. "The effect of zinc supplementation on plasma cholesterol levels." Nutrition research (1984)
Roozbeh, Jamshid. "Effect of zinc supplementation on triglyceride, cholesterol, LDL, and HDL levels in zinc-deficient hemodialysis patients." Renal failure (2009)
Schissel, Scott L. "The cellular trafficking and zinc dependence of secretory and lysosomal sphingomyelinase, two products of the acid sphingomyelinase gene." Journal of Biological Chemistry (1998)
 
Last edited:

Koveras

Member
Joined
Dec 17, 2015
Messages
719
Pellagra is fairly well understood, but there is still some persistent mythology surrounding the etiology. Everyone knows that niacin is the characteristic deficiency, but few are aware of the central importance that leucine plays in this. The somewhat low tryptophan and niacin content of corn is stressed, with little attention given to the main causative agent—if any.

Sorgham causes pellagra, yet has a fair amount of tryptophan and and free niacin. The most salient commonality between sorgham and corn is their extraordinarily high leucine concentrations, as expressed as the ratio to total protein.

'A comparison of the chemical composition of rice, jowar, and maize shows that the nicotinic acid content of jowar is nearly similar to that of rice. The tryptophan content of jowar varies widely, certain strains having nearly as high a content of tryptophan as rice, while certain others have somewhat lower values. Both jowar and maize have, however, one common feature with regard to their amino acid composition: a high content of leucine.' ―Gopalan

View attachment 7627 click to embiggen

'Experimental pellagra was produced in six adult monkeys by feeding diets containing jowar. Clinical and pathological features of this syndrome were indistinguishable from those seen in a group which developed the deficiency on maize diet.' ―Gopalan

What is unique about leucine is its ability to increase the elimination of nicotinic acid (B₃). In a study on adult males over fifty years ago, Gopalan showed the extent of this effect (using only five grams of leucine):

'The rise in N.M.N. [N‐methyl nicotinic acid] excretion brought about by 5 grams L‐leucine daily represented an increase of nearly 50% over the basal level.'―Gopalan

View attachment 7629click to embiggen

'The increase in N.M.N. excretion brought about by supplementation with 5 grams of L‐leucine daily would roughly correspond to the metabolism of an additional 3–5 milligram nicotinic acid daily.' ―Gopalan

This is a common observation, seen in animals of all types. Isoleucine or valine doesn't do this; this effect is particular to leucine.

Gopalan, C. "Leucine and pellagra." The Lancet (1960)
Gopalan, C. "Leucine and pellagra." Nutrition reviews (1968)

Nixtamalization is process where the corn is ground, mixed with water, mixed with alkali, and then strained. This represents a separation procedure, and is known to ameliorate the pellagric effect of corn. The change in amino acid composition has been studied, with significant reductions in the leucine content observed.

'From these figures the average amino acid changes were then calculated. There was a 21.0% decrease for leucine, 18.7% for arginine, 12.5%, for cystine, 11.7% for histidine, and 5.3% for lysine. Of the nonessential amino acids, changes were found in proline, serine, and glutamic acid, amounting respectively to a decrease of 8.7, 7.1, and 6.3%.' —Bressani

View attachment 7630 click to embiggen

'On the other hand, an average of 21% of leucine was lost in the process, a change which should improve the biological value of tortilla protein by partially correcting the isoleucine to leucine disproportion.' —Bressani

This is best explained by the fact that the increased pH causes a precipitation of the protein zein, the alcohol‐soluble fraction. This is then discarded with the water, along with much of the leucine content. Nixtamalization represents a balancing of the amino acid profile. The idea that this process serves to 'liberate niacin' is naïve, considering the fact that sorghum—and even leucine itself—has been shown to cause pellagra. Reading mythological narratives about 'bound niacin' leaves the reader befuddled; it is never explained what it's bound to. Accepting this is akin to accepting the notion that corn has a peculiar and ill‐defined ability to bind niacin, an effect reversed by alkalinity in vitro but not by alkalinity in vivo (duodenal). Moreover, the mythological resilient niacin–protein bond is necessarily unaffected by the hydrochloric acid, the pepsin, the trypsin, and the twelve hours of bacterial action in the digestive tract.


Kodicek, E. "The availability to pigs of nicotinic acid in tortilla baked from maize treated with lime-water." British Journal of Nutrition (1959)
Bressani, Ricardo. "Lime-heat effects on corn nutrients, effect of lime treatment on in vitro availability of essential amino acids and solubility of protein fractions in corn." Journal of Agricultural and Food chemistry (1958)

Why exactly would leucine—of all things—increase the elimination of niacin? So far, I have yet to see an acceptable answer for this. All the articles I've read on this topic leave the question open; there has been little attempt to explain why this should be. Naturally, there are those who think responses like this happen by accident; the explanation that 'leucine inhibits quinolinate phosphoribosyl transferase' (wikipedia.org) is an acceptable explanation for those people.

'Nature does not indulge in luxuries and if there is such a widely spread and highly active enzyme, it must have something very important to do...' ―Albert Szent‐Györgyi

But this explanation fails, for example, to explain why leucine increases tryptophan oxygenase activity; the entire kyneurenine pathway is increased, and shifted. Relatively small changes in leucine divert the kyneurenine pathway from the niacin arm to the picolinate arm:

'To understand the biochemical basis of leucineinduced changes in tryptophan-niacin metabolites, the effects of dietary leucine on the enzymes involved in tryptophan-niacin metabolism were investigated. The enzymes studied were tryptophan oxygenase, 3-hydroxyanthranilate oxygenase, picolinate carboxylase, quinolinate phosphoribosyltransferase and nicotinate phosphoribosyltransferase.' ―Narasinga


'A decreased activity of quinolinate phosphoribosyltransferase may also partly explain the increased quinolinic acid excretion observed in the presence of excess of leucine in the diet (Raghuramulu et al., 1965a; Belavady et al., 1963). The fact that leucine in the presence of added niacin decreased the enzyme activity without affecting quinolinic acid excretion (Raghuramulu et al., 1965a) suggests other mechanisms contributing to increased quinolinic acid excretion.' ―Narasinga

The data does not suggest a simple inhibition of one enzyme; the data suggests a purposeful adaption to excessive leucine, forming picolinate at the expense of niacin.

Excessive amino acids are generally decarboxylated first, then perhaps deanimated. First glance at leucine gives hints about what it could be used for: Leucine's carbon skeleton—sans carbon dioxide—is essentially a saturated isoprene, inviting the speculation that it could be used in cholesterol synthesis. This speculation turns out to be correct, and ¹⁴C‐leucine has been shown to be incorporated into sterols in three Leishmania species—and even in rats:

'The results presented here demonstrate that leucine acts as a major precursor to sterols in several Leishmania species and also in the closely related organism E. monterogeii. Some Leishmania species derived considerably more of their sterol from a leucine source of carbon than did others (Table 3) but there was no apparent correlation between the extent of leucine utilization for sterol production and the origin of the organism as an Old World or New World species.' ―Ginger

View attachment 7635 click to embiggen

'The conversion of leucine to cholesterol in muscle tissue was about 200 times that of acetate and about 25 times that of mevalonate. Utilisation of leucine for cholesterol synthesis was greater than that of acetate and of mevalonate even in intestine and kidney, whereas in liver homogenate acetate and mevalonate were better precursors than leucine.' ―Miettinen

In both protazoa and mammals, leucine can serve as a substrate for steroid synthesis—a fact of central importance to lecucine‐induced pellagra.

Szent-Györgyi, Albert. "The living state and cancer." Proceedings of the National Academy of Sciences (1977)
Rao, BS Narasinga. "Effect of leucine on enzymes of the tryptophan–niacin metabolic pathway in rat liver and kidney." Biochemical Journal (1973)
Ginger, Michael L. "The biosynthetic incorporation of the intact leucine skeleton into sterol by the trypanosomatid Leishmania mexicana." Journal of Biological Chemistry (2001)
Miettinen, T. A. "Comparison of leucine with mevalonate and acetate as a precursor of tissue and serum cholesterol in the rat." Annales medicinae experimentalis et biologiae Fenniae (1971)
Ginger, Michael L. "Utilization of leucine and acetate as carbon sources for sterol and fatty acid biosynthesis by Old and New World Leishmania species, Endotrypanum monterogeii and Trypanosoma cruzi." The FEBS Journal (2000)

Picolinate is no stranger to biology, and perhaps its most particular feature is its ability to chelate zinc. Even commercially, zinc is commonly sold as a picolinate chelate. This is a high‐affinity bond which has biological importance. Picolinate supplementation increases the absorption of dietary zinc, and it wouldn't be a stretch to imagine endogenous picolinate increases the absorption of zinc. This turns out to be true, as was proven by G.W. Evans:

'Those investigators noted that the metabolism of tryptophan was impaired in children who were affected with acrodermatitis enteropathica and suggested that the genetic defect in this disease involved an enzyme in the pathway from tryptophan to nicotinic acid. We believed that this malady resulted from an impaired production of an essential zinc-binding ligand. We thus investigated the possibility that a tryptophan metabolite might be the long sought after zinc binding ligand.' ―Evans

'Rats fed a zein-based diet (20 percent protein) supplemented with lysine but not with tryptophan absorbed only 59 percent of the daily dietary zinc intake. Rats fed the zein diet supplemented with both lysine and tryptophan absorbed 98 percent of the dietary zinc intake, and rats fed the zein diet supplemented with lysine and picolinic acid absorbed 75 percent of the dietary zinc intake (Table 1).' ―Evans


'These observations establish the fact that zinc absorption is affected by levels of both dietary tryptophan and pyridoxine. Furthermore, the results demonstrate that supplemental picolinic acid ameliorates the impaired zinc absorption caused by a deficiency of either tryptophan or pyridoxine. Because picolinic acid is a metabolic product of tryptophan and depends upon pyridoxine for its production, these results provide strong evidence that endogenous picolinic acid is essential for normal zinc absorption.' ―Evans

'The studies reviewed suggest that zinc absorption proceeds as follows: in the exocrine cells of the pancreas the metabolism of tryptophan produces picolinic acid which is secreted into the lumen of the intestine. In the lumen, picolinic acid coordinates with Zn²⁺ to form a complex which facilitates the passage of Zn²⁺ through the luminal membrane, across the absorptive cell and through the basolateral membrane of the cell.' ―Evans

This is another fact to keep in mind—a necessary step in explaining why the body does what it has been shown to do, in response to excess leucine.

Evans, G. W. "Normal and abnormal zinc absorption in man and animals: the tryptophan connection." Nutrition reviews (1980)
Seal, Christopher J. "Effect of dietary picolinic acid on the metabolism of exogenous and endogenous zinc in the rat." The Journal of nutrition (1985)

Zinc increases cholesterol biosynthesis. This is another consistent finding, which is observed in humans with zinc supplementation.

'On day 43, there was a significant elevation in the serum total cholesterol for subjects in the zinc-supplemented group (191.44 mg/dL) compared with the control group (151.42 mg/dL). No significant changes were noted in the serum total cholesterol in the control group from day 0 (146.61 mg/dL) to day 43 (151.42 mg/dL).' ―Roozbeh

This is also observed in rats, and the inclusion of zinc to their diet predictable lead to hypercholesterolemia.


'However, several studies have shown a role for zinc in determining serum cholesterol and triglyceride levels: a zinc-deficient diet induces hypotriglyceridemia in rats and hypocholesterolemia in rats and pigs; zinc supplemented swines had higher cholesterol levels than their unsupplemented counterparts during the first 4 weeks of treatment; Lei using a moderately copper-deficient diet supplemented with zinc obtained a hypercholesterolemia in the rat.' ―Katya-Katya

View attachment 7638 click to embiggen

'At the end of the experiment, the zinc-supplemented rats had a 50% higher cholesterol concentration than the control rats.' ―Katya-Katya

The regulatory cascade which orchestrates cholesterol synthesis is zinc‐dependent. The enzyme required in the second canonical stage needs zinc ions to function, a fact which can explain how dietary zinc can effect cholesterol levels so powerfully.

'Site-2-protease (S2P), a member of the family of zinc metalloproteases, catalyzes hydrolysis of the second proteolytic reaction on SREBP [sterol regulatory element binding protein], which releases a soluble transcription factor (the amino-terminal fragment of SREBP). The soluble transcription factor enters the nucleus, where it binds to direct repeat sterol response elements in promotor regions, activating transcription of sterol-regulated cholesterogenic genes. Genes under this regulatory control include, at least, LDL receptor, HMG-CoA synthase, HMG-CoA reductase, farnesyl diphosphate synthase, squalene synthase, lanosterol synthase, and lanosterol 14α-methyl demethylase cytochrome P450. Activation of these genes restores intracellular cholesterol levels.' ―Risley

''The first RIP system to be molecularly characterized was the cleavage of the membrane-anchored transcription factor SREBP (sterol regulatory element–binding protein) by a metalloprotease known as site-2 protease (S2P). This cleavage releases a transcription factor, which translocates into the nucleus of the cell and activates genes involved in synthesis and uptake of cholesterol and fatty acids.' ―Feng

Besides site‐2‐protease, other zinc metalloproteases are involved in lipid synthesis. A study conducted in 1998 shows the zinc dependency of sphingomyelinase directly.

'We then tested this purified L-SMase for zinc dependence and found that its enzymatic activity was increased 4.7-fold in the presence of Zn²⁺.' ―Schissel

View attachment 7639 click to embiggen

'the data in this report strongly support the conclusion that this enzyme is, indeed, a zinc‐activated enzyme.' ―Schissel

The enzyme responsible for the second, and indispensible, step in canonical cholesterol regulation has been characterized. It has been found to contain a considerable amount of zinc, bound tightly, coordinated by histidine (of course):

'S2P has six transmembrane segments, TM1 through TM6. The catalytic zinc atom is located ~14 Å from the lipid membrane surface. Zinc is coordinated by three amino acids, His⁵⁴ and His⁵⁸ in TM2, and Asp¹⁴⁸ in TM3, which are highly conserved in all S2P proteins.' ―Feng

'As previously hypothesized, the catalytic zinc atom is coordinated by three amino acids that are invariant among all S2P family proteins: His⁵⁴ and His⁵⁸ from helix a2 and Asp¹⁴⁸ from the N‐terminal end of helix [...]. The zinc atom is located ~14 Å below the lipid membrane surface from the cytosolic side.' ―Feng

'Quantitative element analysis by inductively coupled plasma emission spectrometry revealed that, compared with the WT protein, the zinc content was 8.2, 44.2, 5.1, and 15.1% for the mutant proteins H54A, E55A, H58A, and D148A, respectively.' ―Feng

Radioactive ¹⁴C‐leucine has been shown to be incorporated into the cholesterol skeleton by mammals, including mice; picolinate has been shown to chelate zinc, and so has tryptophan (ostensibly via picolinate); zinc has unambiguously been shown to increase cholesterol synthesis; what follows from this is an explanation why dietary leucine increases the production of picolinate at the expense of niacin: It purposefully does so as a device to increase the absorption of the obligatory dietary zinc for cholesterol synthesis, the most efficient way for the body to deal with excessive leucine.

Risley, John M. "Cholesterol biosynthesis: Lanosterol to cholesterol." J. Chem. Educ (2002)
Feng, Liang. "Structure of a site-2 protease family intramembrane metalloprotease." Science (2007)
Katya-Katya, M. "The effect of zinc supplementation on plasma cholesterol levels." Nutrition research (1984)
Roozbeh, Jamshid. "Effect of zinc supplementation on triglyceride, cholesterol, LDL, and HDL levels in zinc-deficient hemodialysis patients." Renal failure (2009)
Schissel, Scott L. "The cellular trafficking and zinc dependence of secretory and lysosomal sphingomyelinase, two products of the acid sphingomyelinase gene." Journal of Biological Chemistry (1998)

How might this relate as well to the stimulation of mTOR/protein synthesis by leucine and the requirement of zinc for tissue growth?

Twenty-five years of mTOR: Uncovering the link from nutrients to growth


"Almost 60% of the zinc in our bodies is in our skeletal muscle. Almost 30% is in our bone. That’s just because those tissues are so big. If we look at some of the smaller organs, we see the highest concentrations in the prostate, followed by the pancreas, with bone not too far behind, most other organs much lower, and the brain is the lowest. But zinc is actually incredibly important to every single tissue of the body, regardless of its concentration there."

"I think that one area that’s overlooked is in bodybuilding. Let’s say that you want to put on 10 pounds of muscle. You need about 20 milligrams of total zinc to add 1 kilogram of body weight, which is 2.2 pounds. So you basically need about 90 milligrams to put on 10 pounds of muscle, and that’s pretty equivalent to what you’d expect a pregnancy to add. If you want to put on 10 pounds of muscle in one month, that’s gonna require 3 milligrams of zinc per day. And if you assume that you’re only absorbing about a third of the zinc from your food, then maybe that’s 9 milligrams of zinc per day, which is pretty significant if you are engaged in intensive bodybuilding.”

Why You Should Manage Your Zinc Status and How to Do It


Screen Shot 2017-12-21 at 9.14.48 AM.png Screen Shot 2017-12-21 at 9.14.55 AM.png Screen Shot 2017-12-21 at 9.15.10 AM.png
 

Travis

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fantastic post @Travis

I had no idea. I believed the niacin myth.
Thanks. I too had just accepted it, and basically accept all Wikipedia explanations until I hear of more accurate ones. But it's not a total myth, and there a bit of truth to it. Some niacin is actually bound to cellulose, covalently, through an ester bond. But this is certainly not unique to corn and can be found in very many grains. And if you look at this video on nixtamalization you'd probably have to come to the conclusion that any 'liberated niacin' would, in fact, be irretrievably lost in the water:


Leucine influences niacin metabolism, an amino reduced 21% through the process of nixtamalization.

The two grains associated with pellagra, sorghum and corn, both have a common peculiarity that most grains do not: a disproportionate leucine:protein ratio.


I had looked into pellagra wondering if interferon-γ was involved since: (1) Tryptophan was involved, and interferon-γ powerfully increases trypophan metabolism as a device to limit pathogens: (2) The skin was involved, and interferon-γ predictably causes skin disorders by upregulating phospholipase A₂: (3) And a potentially allergenic glutamine–proline‐rich seed storage protein was involved, in corn. After a few minutes I had realized that corn protein is mostly hypoallergenic—like rice—but that leucine and zinc play an important role.

I found an article by people who see pellagra along these lines, and even present a logical chemical mechanism for the skin changes:

'Although pellagra was recognized 50 y ago as a deficiency disorder controlled by nicotinic acid, an understanding of the biochemical defect responsible for the skin, hair, and intestinal abnormalities is lacking. Over the years, observations repeatedly have indicated that tryptophan is essential for their prevention and that nicotinic acid deficiency may not be responsible for all clinical manifestations. Thus, deficiency of pyridoxine, which blocks the tryptophan pathway, causes pellagra‐like dermatitis, which is not prevented by a diet with normal nicotinic acid content. Diets rich in corn products cause pellagra, although they meet the recommended dietary allowances (RDA) for nicotinic acid, apparently because they are low in tryptophan. Experiments showing nicotinic acid to be unavailable in corn have been disproven. Adding milk to a corn-based diet was shown to prevent pellagra apparently because milk is rich in trptophan but lower in nicotinic acid than corn. Similar observations were reported from India where pellagra is common among people living on sorghum-based diets but not among those living on rice, although their nicotinic acid and tryptophan intakes are similar. This phenomenon since has been attributed to excess leucine, which alters tryptophan metabolism but does not inhibit the utilization of dietary nicotinic acid. Demonstration of low uricanic acid concentrations in the skin of patients with pellagra may explain the sensitivity to sunlight typical of the disease because uricanic acid absorbs ultraviolet light. This observation gains interest because the abnormality could result from zinc deficiency, which increases the catabolism of histidine, the immediate precursor of uricanic acid. Although Zn²⁺ and nicotinic acid deficiency often coexist in patients with pellagra because their diets tend to be deficient in multiple nutrients, it is possible, in light of recent observations, that Zn²⁺ deficiency is a direct result of tryptophan deficiency. A link between tryptophan and Zn²⁺ deficiency previously was suggested by us for the following reasons: 1) Similarities exist between the dermatitis of pellagra, Zn²⁺, and pyridoxal deficiency; 2) In addition to increased kynurenine, previously reported by several investigators of a genetic Zn²⁺ deficiency called acrodermatitis enteropathica (AE), we observed in three patients with AE decreased serum levels of picolinate, which is an end product of tryptophan metabolism; 3) Lack of pyridoxine, which blocks the tryptophan pathway to nicotinic acid and picolinate, results in fatty acid abnormalities and has teratogenic effects similar to Zn²⁺ deficiency; 4) Low-Zn²⁺ absorption due to protein deficiency is correctable by supplementation with tryptophan or picolinic acid, a Zn²⁺ binding ligand.' ―Krieger, Ingeborg, and Statter
The authors take the position that it's really tryptophan's metabolite picolinic acid which is of primary concern; the skin changes seen in pellagra are essentially a result of of zinc deficiency. This could have some truth to it, as zinc deficiency is known to cause extreme skin pathology.

The authors even present a mechanism on how zinc deficiency causes skin changes. Besides melanin, the body has another sunscreen molecule called urocanic acid—metabolite of histidine. This has been shown in a quite a few experiments to block UV light:

'There was a distinct elevation in the minimal erythema dose, indicating that the compound has the capacity to act as a sunscreen. An increase in the transmission of ultraviolet light of 10–15% by epidermis from which urocanic acid has been extracted is indicative of the role of the endogenously present material. The mechanism for this protection afforded by urocanic acid has been elaborated by our studies. Anglin et al (28) had previously reported that irradiation of skin with ultraviolet light produces a trans to cis isomerization of urocanic acid, and Baden, Pathak and Butler (15) confirmed this with nuclear magnetic resonance technics. The reaction occurs most effectively with ultraviolet radiation and at energy levels capable of producing erythema. We believe that this trans‐cis isomerization induced by light represents a physiological mechanism for absorption and dissipation of solar radiation.' ―Baden

And it has been shown, in rats, that a ditary zinc deficiency will result in lowered histidine levels in the skin—by roughly 50% in the study below. This would lead to lower urocanic acid, and higher UV permeability.

'Impairment of cystine metabolism in rats deficient in zinc has been previously reported. Histidine, like cysteine, is a natural chelating agent and is loosely bound to plasma Zn²⁺, suggesting that the amino acid‐bound fraction of Zn²⁺ may have an important role in biological transport of this element.' ―Hsu

zinc5.png click to embiggen

'Thus, Zn²⁺ is an important factor in regulating histidine metabolism through the urocanic acid pathway.' ―Hsu
This would make trypophan primary and niacin secondary. Tryptophan is necessary to create the picolonate necessary for zinc absorption. A study on pellagric alcoholics indicates that zinc supplementation can increase niacin excretion, and that pellagrics have low zinc levels.

'The present results demonstrate that the patients with pellagra had protein calorie malnutrition upon admission to the hospital and reduced plasma Zn²⁺ and tryptophan levels in relation to normal individuals, as well as a decreased urinary excretion of niacin metabolites.' ―Vannucchi

This zinc could be increasing the production of niacin by lowering the picolinate requirement.

Leucine further exacerbates the issue by providing a substrate for cholesterol synthesis, apparently increasing the requirement for zinc in the liver. The low tryptophan, low zinc, low niacin, and high leucine in corn all appear to conspire together to create the skin changes seen in pellagra. There's a few redox mechanisms out there involving NADH and glutathione, for the skin changes, but I think the one involving urocanic acid is more believable.

Hsu, Jeng M. "Effect of zinc deficiency on histidine metabolism in rats." The Journal of nutrition (1982)
Baden, Howard P. "The Metabolism and Function of Urocanic Acid in Skin." Journal of Investigative Dermatology (1967)
Vannucchi, Helio. "Interaction of niacin and zinc metabolism in patients with alcoholic pellagra." The American journal of clinical nutrition (1989)
Krieger, Ingeborg, and M. Statter. "Tryptophan deficiency and picolinic acid: effect on zinc metabolism and clinical manifestations of pellagra." The American journal of clinical nutrition (1987)

How might this relate as well to the stimulation of mTOR/protein synthesis by leucine and the requirement of zinc for tissue growth?

Twenty-five years of mTOR: Uncovering the link from nutrients to growth


"Almost 60% of the zinc in our bodies is in our skeletal muscle. Almost 30% is in our bone. That’s just because those tissues are so big. If we look at some of the smaller organs, we see the highest concentrations in the prostate, followed by the pancreas, with bone not too far behind, most other organs much lower, and the brain is the lowest. But zinc is actually incredibly important to every single tissue of the body, regardless of its concentration there."

"I think that one area that’s overlooked is in bodybuilding. Let’s say that you want to put on 10 pounds of muscle. You need about 20 milligrams of total zinc to add 1 kilogram of body weight, which is 2.2 pounds. So you basically need about 90 milligrams to put on 10 pounds of muscle, and that’s pretty equivalent to what you’d expect a pregnancy to add. If you want to put on 10 pounds of muscle in one month, that’s gonna require 3 milligrams of zinc per day. And if you assume that you’re only absorbing about a third of the zinc from your food, then maybe that’s 9 milligrams of zinc per day, which is pretty significant if you are engaged in intensive bodybuilding.”


Why You Should Manage Your Zinc Status and How to Do It


View attachment 7641 View attachment 7642 View attachment 7643

This is interesting stuff, and a pathway some early Pellagra researchers had likely discovered without realizing it. The body has a zinc‐sensing protein called sestrin‐2 involved in the mTORC pathway, an acronym standing for 'mammalian target of rapamycin complex'—another protein named after the drug in binds to, similar to FK‐506 and the cyclophilins.

'Subsequent in vitro studies demonstrated that the Sestrin2-GATOR2 interaction is sensitive specifically to leucine, which binds Sestrin2 with a dissociation constant of ~20 mM.' ―Saxton

zinc7.png zinc6.png click to embiggen

'Human embryonic kidney (HEK)–293T cells expressing a Sestrin2 mutant that cannot bind leucine fail to activate mTORC1 in response to leucine, suggesting that Sestrin2 is the primary leucine sensor for the mTORC1 pathway in these cells.'―Saxton

This pathway is well‐known to be involved in cholesterol synthesis, but the exact manner in which it does so is not very well‐defined. It seems the proteins involved in the mTORC complex—including the leucine‐sensing sestrin—are involved somehow in binding, degrading, or facilitating the sterol regulatory element binding proteins (SREBPs): transcription factors which interact with the DNA directly. The zinc‐sensing metalloenzyme site‐2‐protease is also involved in controlling SREBPs in the cytosol, by liberating it from it's inactive binding site. Besides sestrin2, the mTORC complex also contains leucyl‐tRNA synthetase, a protein whose function is to incorporate the amino acid leucine into transfer RNA—a prerequisite for protein synthesis. So it seems as though the cellular machinery dealing with leucine‐sensing has evolved a secondary function of controlling sterol synthesis genes. This makes sense because leucine is the amino acid inherently most suitable to become cholesterol: Leucine's decarboxylated skeleton is essentially saturated isoprene.

'Leucine binding to Sestrin2 also alters its melting temperature, implicating a leucine-induced conformational change.' ―Lee

'Furthermore, Sestrin knockout mice are predisposed to various systemic metabolic defects, including fat accumulation and insulin resistance.' ―Lee

Certainly interesting, and a good reason to take all five competing amino acids together for lowering tryptophan—leucine, isoleucine, tyrosine, phenylalanine, and valine—and not just leucine alone; this would activatate the mTOR pathway. Taking zinc picolinate could perhaps spare niacin, as it negates the need for picolinate production. The increased cholesterol synthesis which can result from taking zinc is probably not something to worry about (Pauling, 1991).

Saxton, Robert A. "Structural basis for leucine sensing by the Sestrin2-mTORC1 pathway." Science (2016)
Posadas-Romero, C. "Cholesterol levels and prevalence of hypercholesterolemia in a Mexican adult population." Atherosclerosis (1995)
Rath and Pauling. "Solution to the Puzzle of Human Cardiovascular Disease: Its Primary Cause is Ascorbate defiency..." J Orthomol (1991)
Wang, B. "The mammalian target of rapamycin regulates cholesterol biosynthetic gene expression and exhibits a rapamycin-resistant transcriptional profile." Proceedings of the National Academy of Sciences (2011)

 
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Amazoniac

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I should note that when I came across this study the link wasn't white or purple: it was blue. I took it as a reinforcing sign to my suspicion that I didn't select it or read it before.
Q: Doesn’t exposure to the sun age you?

This effect is variable, and depends on our hormones and diet.

The unsaturated oils have been identified as a major factor in skin aging. For example, two groups of rabbits were fed diets containing either corn oil or coconut oil, and their backs were shaved, so sunlight could fall directly onto their skin. The animals that ate corn oil developed prematurely wrinkled skin, while the animals that ate coconut oil didn’t show any harm from the sun exposure. In a study at the University of California, photographs of two groups of people were selected, pairing people of the same age, one who had eaten an unsaturated fat rich diet, the other who had eaten a diet low in unsaturated fats. A panel of judges was asked to sort them by their apparent ages, and the subjects who consumed larger amounts of the unsaturated oils were consistently judged to be older than those who ate less, showing the same age-accelerating effects of the unsaturated oils that were demonstrated by the rabbit experiments.

While it is important to avoid overexposure to ultraviolet light, the skin damage that we identify with aging is largely a product of our diet.
 
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Travis

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I should note that when I came across this study the link wasn't white or purple: it was blue. I took it as a reinforcing sign to my suspicion that I didn't select it or read it before.
Ignoring niacin for one moment, one is still compelled to see the pellagra‐like skin changes seen in zinc deficiency. Have you seen pictures of this?
 

Travis

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Interesting study. There seems to be a cascade after sun damage, starting with cytokines and ending in prostaglandins and nitric oxide. It was a mouse–ear study, showing a correlation between prostaglandin E₂ and skin damage. They did not measure zinc or urocanic acid levels.

I'll acknowledge the Sugita mouse–ear sunburn study, and raise you one De Fabo mouse–ear sunburn study:

Reilly, Sheryl K., and Edward C. De Fabo. "DIETARY HISTIDINE INCREASES MOUSE SKIN UROCANIC ACID LEVELS AND ENHANCES UVB‐INDUCED IMMUNE SUPPRESSION OF CONTACT HYPERSNSITIVITY." Photochemistry and photobiology (1991)

The language is a bit peculiar, as De Fabo uses the term 'immunosuppression' to mean 'lack of damage.' He apparently does this because he thinks that urocanic acid actively acts on the histamine receptors to either prevent immune activation or actively cause supression. This is not a crazy idea, as the structural difference between histamine and urocanic acid is small, but many people would interpret these effects as deriving simply from the ability of urocanic acid to absorb UV light (akin to a sunblock, or melanin). It absorbs strongly in the UVB region and undergoes a cis–trans isomerism similar to retinol.

'A bank of 6 Westinghouse Pa40 sunlamps, which emit a broadband of UV from 150 to 400 nm containing 60-65% UVB (180-310) with peak emission at 313 nm was used in this study.' ―De Fabo

De Fabo fed one group of mice excess histidine—precursor for urocanic acid—and irradiated them spectacularly and with maximum prejudice using high‐intensity Westinghouse tanning lamps: Ear burns followed and mice were unhappy.

'Results of this comparison showed that at 4.8 and 7.1 kJ/m², irmnunosuppression of CHS was significantly increased (i.e. ear swelling was significantly reduced) in the histidine-fed mice but not in tho animals fed control chow.' ―De Fabo

zinc9.png click to embiggen: Graph showing reduced ear swelling in histidine‐fed mice.

'Taken as a whole, the dose-response data in Fig. 2 indicate that in the histidine-fed mice (closed circles, Figs. 2A and 2B), an increase in sensitivity to UVB-induced immune suppression relative to control mice appears to exist. [...] The reason for the reversal in ear swelling at the highest doses given to histidine-fed mice is unknown.' ―De Fabo

The histidine‐fed mice, predictably, had higher urocanic acid levels in their skin. One problem—that I can think of—with the idea of this mainly being the effect of urocanic acid working on the histamine receptors, is: Histamine would be increased as well as it's the only precursor to both.

'At the end of the 3-week feeding period, and immediately following UV exposure, the mice were sacrificed and the UCA levels in their dorsal skin measured by HPLC.' ―De Fabo

zinc8.png click to embiggen: Graph showing increased urocanic acid in histidine‐fed mice.

'These new data argue, therefore, that an increase in the dietary level of histidine can lead to enhanced levels of UVB-induced innnunosuppression.' ―De Fabo

De Fabo has done other studies on urocanic acid and the skin. He has authored an impossible‐to‐source one on histidase knockout mice, as well as a few others. I see urocanic acid right now, essentially, as a water-soluble UV-absorber under the dietary influence of histidine and zinc (and a few enzymes). A study conducted to determine the amino acid requirement for histidine noticed skin changes in the deficient group.

'Subjects felt unwell, and in five cases a skin lesion consisting of fine scales, dry skin, and mild erythema developed.' ―Kopple

So regardless of any effect niacin may have on the skin, alone, it cannot be argued that histamine also has an effect. There is some evidence to indicate that the profound skin anomalies seen in zinc deficiency is a result of lowered UV-absorbing urocanic acid consequent of disturbed histidine metabolism. Urocanic acid is a molecule which absorbs UV radiation—converting it to thermal/kinetic energy through cis–trans isomerism.

'This increase in concentration of skin trans-UCA makes it more likely that UVB photons will be absorbed, thereby increasing trans to cis isomerization and, as a result, immune suppression. Thus, by starting with a higher concentration of skin trans-UCA in the histidine-fed mice, a threshold level of immune-suppressing cis-UCA molecules could be reached at a much lower UVB dose than normally required.' ―De Fabo

zinc10.png click to embiggen: Graph showing both cis and trans isomers of urocanic acid in mouse skin.

'The data presented in this paper have demonstrated that if the amount of trans-UCA in BALB/c mouse skin is increased by feeding the mice a diet rich in histidine for 3 weeks [...] This finding of enhanced UVB-induced immune suppression demonstrates that an increase in sensitivity to UVB-induced immune suppression can be linked to diet, and specifically identifies the dietary component as the amino acid, L-histidine, the natural metabolic precursor of trans-UCA.' ―De Fabo

While the histamine receptor interactions are interesting, they could be of less significance that the direct UVB absorption capacity of urocanic acid.

'Urocanic acid has been shown to be capable of binding to DNA (Morrison et al., 1985) and Matheson and Reeve (1990) have shown that cimetidine, which is capable of binding to the histamine receptor on T cells, substantially inhibits the outgrowth of UV-induced skin tumors. They suggest that this may be due to a competitive inhibition of cis-UCA binding to the same histamine receptor (Mitchell et al., 1990). If binding of cis-UCA with such receptors occurs, this may cause release of cytokines or other factors which regulate the immune response. If this is the case, once a threshold level of cis-UCA is reached and immune suppression is initiated, only small increments in cis-UCA concentration may be needed to cause additional suppression up to a level of saturation.' ―De Fabo

There are many findings which don't seem to support a biologically-relevant signalling role for urocanic acid, a molecule probably best seen in photochemical terms.

'The reason for a lack of correlation between immune suppression and cis-UCA formation at these higher doses is unknown.' ―De Fabo

'Unirradiated mice on both diets showed similar levels of sensitization to TNCB.' ―De Fabo

But you could find out, by reading some urocanic acid studies not involving UVB radiation. It's well-known that histamine is involved in inflammation, and would be expected to be involved in sun damage (concomitant with prostaglandins, cytokines, and nitric oxide). Another issue is that it has a carboxyl group in the place where histidine and cimetedine have an amino group. The carboxylic acid group and the amino group have opposite charges in water.

Kopple, J. D., and M. E. Swendseid. "Evidence that histidine is an essential amino acid in normal and chronically uremic man." Journal of Clinical Investigation (1975)
Reilly, Sheryl K., and Edward C. De Fabo. "DIETARY HISTIDINE INCREASES MOUSE SKIN UROCANIC ACID LEVELS AND ENHANCES UVB‐INDUCED IMMUNE SUPPRESSION OF CONTACT HYPERSNSITIVITY." Photochemistry and photobiology (1991)
 
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sugarbabe

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Wikipedia says this: "The first mechanism is simple dietary lack of niacin. Second, it may result from deficiency of tryptophan,[3] an essential amino acidfound in meat, poultry, fish, eggs, and peanuts[8] that the body converts into niacin. Third, it may be caused by excess leucine, as it inhibits quinolinate phosphoribosyl transferase (QPRT) and inhibits the formation of Niacin or Nicotinic acid to Nicotinamide mononucleotide (NMN) causing pellegra like symptoms to occur.[9. "

So looks like the research is coming out.
 

Travis

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Wikipedia says this: "The first mechanism is simple dietary lack of niacin. Second, it may result from deficiency of tryptophan,[3] an essential amino acidfound in meat, poultry, fish, eggs, and peanuts[8] that the body converts into niacin. Third, it may be caused by excess leucine, as it inhibits quinolinate phosphoribosyl transferase (QPRT) and inhibits the formation of Niacin or Nicotinic acid to Nicotinamide mononucleotide (NMN) causing pellegra like symptoms to occur.[9. "

So looks like the research is coming out.
No mention of zinc or picolinate. Wikipedia also says this:

'Nixtamalization corrects the niacin deficiency, and is a common practice in Native American cultures that grow corn.' ―Wikipedia

Yet Krieger says this (quoted previously above):

'Experiments showing nicotinic acid to be unavailable in corn have been disproven.' ―Krieger, Ingeborg, and Statter

And Wikipedia makes no mention that nixtamalization reduces the leucine content by 21%—a fact likely of more importance than any liberation of niacin that would, of course, be lost in the calcium hydroxide water.

Wikipedia says this:

'Third, it may be caused by excess leucine, as it inhibits quinolinate phosphoribosyl transferase (QPRT) and inhibits the formation of Niacin or Nicotinic acid to Nicotinamide mononucleotide (NMN) causing pellegra like symptoms to occur.' ―Wikipedia

Yet Narasinga says this (quoted previously above):

'A decreased activity of quinolinate phosphoribosyltransferase may also partly explain the increased quinolinic acid excretion observed in the presence of excess of leucine in the diet (Raghuramulu et al., 1965a; Belavady et al., 1963). The fact that leucine in the presence of added niacin decreased the enzyme activity without affecting quinolinic acid excretion (Raghuramulu et al., 1965a) suggests other mechanisms contributing to increased quinolinic acid excretion.' ―Narasinga

I would be the Narasinga experimental study was the most in‐depth study on the metabolism of excess leucine and the kynurenine pathway. Wikipedia did not cite this, but cited a much older review article (at best, since that statement had ambiguous attribution). There is no evidence that it 'inhibits' this enzyme; what is more likely is that leucine actives events which transcriptionally downregulate the mRNA for said enzyme. The liver's main leucine sensor is called sestrin‐2, which it binds with very high‐affinity and controls sterol regulatory element binding proteins.
 
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sugarbabe

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No mention of zinc or picolinate. Wikipedia also says this:

'Nixtamalization corrects the niacin deficiency, and is a common practice in Native American cultures that grow corn.' ―Wikipedia

Yet Krieger says this (quoted previously above):

'Experiments showing nicotinic acid to be unavailable in corn have been disproven.' ―Krieger, Ingeborg, and Statter

And Wikipedia makes no mention that nixtamalization reduces the leucine content by 21%—a fact likely of more importance than any liberation of niacin that would, of course, be lost in the calcium hydroxide water.

Wikipedia says this:

'Third, it may be caused by excess leucine, as it inhibits quinolinate phosphoribosyl transferase (QPRT) and inhibits the formation of Niacin or Nicotinic acid to Nicotinamide mononucleotide (NMN) causing pellegra like symptoms to occur.' ―Wikipedia

Yet Narasinga says this (quoted previously above):

'A decreased activity of quinolinate phosphoribosyltransferase may also partly explain the increased quinolinic acid excretion observed in the presence of excess of leucine in the diet (Raghuramulu et al., 1965a; Belavady et al., 1963). The fact that leucine in the presence of added niacin decreased the enzyme activity without affecting quinolinic acid excretion (Raghuramulu et al., 1965a) suggests other mechanisms contributing to increased quinolinic acid excretion.' ―Narasinga

I would be the Narasinga experimental study was the most in‐depth study on the metabolism of excess leucine and the kynurenine pathway. Wikipedia did not cite this, but cited a much older review article (at best, since that statement had ambiguous attribution). There is no evidence that it 'inhibits' this enzyme; what is more likely is that leucine actives events which transcriptionally downregulate the mRNA for said enzyme. The liver's main leucine sensor is called sestrin‐2, which it binds with very high‐affinity and controls sterol regulatory element binding proteins.
Thanks for breaking that down haha. Are you a researcher? Scientist? What are you? :woot:

You should edit the entry. We need people like you on there!
 

Travis

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Thanks for breaking that down haha. Are you a researcher? Scientist? What are you? :woot:

You should edit the entry. We need people like you on there!
I edited the page on refractive error once. I had replaced this paragraph:

'Near-sightedness is due to the length of the eyeball being too long, far-sightedness the eyeball too short, astigmatism the cornea being the wrong shape, and presbyopia aging of the lens of the eye such that it cannot change shape sufficiently.[1] Some refractive errors occur more often among those whose parents are affected.[1]Diagnosis is by eye examination.[1]' ―Wikipedia

...with a much better one. A day later I got a message from the administrator 'Doc James,' and a flame war was begun. He mumbled something stupid about citing textbooks: I had responded by informing him that experimental findings trump textbooks, nothing reflects reality more than actual evidence.

Besides it being unbelievable, I have read a few clinical studies remarking that the chamber depth (eye length) did not change concomitantly with the refractive changes induced by insulin.

So there you have it. The wikipedia.org pellagra page isn't too bad, but I think something needs to be said about zinc. There was actually a study that had measured zinc on the skin in pellagra, but it was written in Spanish. Perhaps it could be worth translating.

Look up pictures of zinc deficiency if you don't think they could be related. Tryptophan makes picolinate, which is then released by the pancreas to increase zinc absorption. Whenever picolinate is increased—assuming constant tryptophan levels—niacin would necessarily be decreased. It's hard to separate tryptophan, picolinate, niacin, and zinc from eachother; they are all related and and change in one would likely effect the others. Corn actually has decent amounts of niacin, but is extremely low in tryptophan.
 
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I have no idea if you've already mentioned this, but I found something and I can't find any results when searching the term.

Basically, I have found a variety of corn that is used to prevent pellagra and as an animal feed, the only difference is that this variety has twice the amount of lysine and tryptophan.

It seems you're correct about pellagra being due to the amino acids, rather than niacin being insoluble until nixtamilzation occurs, which is what I've always taken as granted to be true.

Quality Protein Maize - Wikipedia

I was just researching for a good source of plant protein (protein hydrolysis is very interesting), and came across this.

This absolutely confirms your theory. Turns out nixtamalized corn isn't magic after all. It still tastes a lot better.
 

Travis

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I have no idea if you've already mentioned this, but I found something and I can't find any results when searching the term.

Basically, I have found a variety of corn that is used to prevent pellagra and as an animal feed, the only difference is that this variety has twice the amount of lysine and tryptophan.

It seems you're correct about pellagra being due to the amino acids, rather than niacin being insoluble until nixtamilzation occurs, which is what I've always taken as granted to be true.

Quality Protein Maize - Wikipedia

I was just researching for a good source of plant protein (protein hydrolysis is very interesting), and came across this.

This absolutely confirms your theory. Turns out nixtamalized corn isn't magic after all. It still tastes a lot better.
There's a tiny bit of truth to the 'mainstream,' watered‐down, pop‐bubblegum version of Pellagra but they have greatly exaggerated one tiny facet and had more‐or‐less neglected some very important issues. Trypotphan seems more important than niacin since it makes picolinate, then released by the pancreas to chelate and absorb Zn²⁺ ions. The skin problems seen in Pellagra could most easily be explained by low zinc; and in fact, the explanations for how a lack of niacin could potentially 'damage the skin' never were very convincing.

Consuming niacin would spare tryptophan, which would then spare picolinate. This would lead to greater Zn²⁺ absorption, better skin, and less Pellagra.
 

charlie

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Does anyone know if @Travis is saying that zinc picolinate should also be administered with niacin to correct Pellegra? Or that the niacin is going to spare zinc and picolinate so no reason to take it(zinc picolinate)? :confused2
 
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Terma

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He was saying pure niacin absorbed quickly spares Trp by feedback after its gut absorption so more Trp would be expected to turn into picolinic acid rather than quinolinic, so niacin would indirectly increase zinc absorption from the gut on its own. It's the kind of result found in: Apparent absorption of copper and zinc from composite vegetarian diets in young Indian men. - PubMed - NCBI. In other words normally it is a good idea to take some copper with the niacin unless you are low in zinc (I clarified the other thread).
 
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