B12 Deficiency And Hypothyroidism

[Birdie]

The above was copied from Amazoniac's further above. It could apply to me. I probably have impaired intestinal function. I'm gluten intolerant. This impaired intestinal function is the reason I do better with injections of B12.

Then, I've dealt with parasitic infections in the past and have some indications of present problems there. I see a connection to my Seborrheic dermatitis and rosacea. To help, I took a weight appropriate dose of Ivermectin a few days ago. Wonder what Peat might think of that...

I will avoid going under with nitrous oxide.

 

[Antonello]

- Vitamin B12 among Vegetarians: Status, Assessment and Supplementation

"A common mistake is to think that the presence of dairy products and eggs in the diet, as in LOV [Library of Virginia], can still ensure a proper intake of Cbl, despite excluding animal flesh. In reality, consumption of such foods, despite containing significant amounts of Cbl, would be sufficient neither on a daily basis nor in order to meet vitamin requirements [18].[*] A Dietary Reference Intake (DRI) of 2.4 μg/day for Cbl in adults is a common chosen value [19,20]. Such an amount is apparently exceeded by American adults, with a mean intake ranging from 4.6 to 6.3 μg/day [21]. However, it is not uncommon to see a moderate deficiency among omnivores in Western countries [22,23]. A recent report by the European Food Safety Authority (EFSA) Panel on Dietetic Products, Nutrition and Allergies established an Adequate Intake (AI) of 4 μg/day for adults, with a mean intake in European countries ranging between 4.2 and 8.6 μg/day [24]."

*This doesn't seem too unlikely given that milk is meant to be ingested as a sole food throughout the day in small amounts at a time.​

"The main source of consumption in the general population comes from animal foods with a significant contribution from milk and dairy products [25]. Losses of up to 50% can occur through food processing which involves cooking, pasteurization and exposure to fluorescent light. This limits its availability, together with a drop in absorption capacity and an increase in Cbl concentration in food [26]. Some researchers claim that the currently recommended intake levels may not be sufficient for an adequate daily intake, with particular regard to aging and the physiological reduction in absorptive capacity [27]. With senescence, the epithelial cells of the stomach reduce their ability to biosynthesize the transporter proteins of Cbl. The gastric secretion ability is necessary both for the dissociation of Cbl from foods and for the binding to the carriers [28]. For these reasons, the American Institute of Medicine recommends a supplementation of Cbl for people of 50 years of age and older [19]. The development of blood and cognitive disorders are rather common aspects found among the elderly population [29].

In the vegetarian diet, there are few sources of Cbl, whilst supplement use is frequently resisted.

Although some plant foods seem to represent a significant source of Cbl [30,31], data in the literature are still insufficient to determine whether Cbl is found in the active form, and whether regular consumption of these foods can be sustainable when the variability in the production processes is taken into account."

"In the cell, the Cbl isoforms are metabolized inside the peroxisome by the reactions of dealkylation, decyanation and reduction, and then released in the specific cell compartment as coenzyme Me-Cbl and Ado-Cbl, according to their cytosolic or mitochondrial fate, respectively [46]. This step is crucial in the activation of the provitamin forms. Other corrinoid compounds do not fulfill the vitamin functions, in all probability due to the binding power of the lower ligand with the cobalt, which does not allow peroxisome activation [45]. It seems that all isoforms, provitamins and coenzymes should follow a mandatory route before being assigned to the appropriate cell district. However, the H-Cbl form may be more reactive, and its use can be facilitated by a number of enzymatic processes through non-specific cellular reactions [47]. If this mechanism were confirmed, the use of already active Cbl cofactors would not represent any provitamin advantage [45]. In 1982, Gimsing et al. analyzed Cbl in tissues from patients with pernicious anemia. After administration of H-Cbl or Cn-Cbl, they found that detected plasma Cbl was dependent on the form administered, dominant in the blood pattern. Results from erythrocytes and liver biopsies showed no differences, irrespective of the Cbl form used, indicating that administered Cbl preparations are converted in vivo to the necessary coenzymes [48]. Although current studies have many limitations and altogether there are no significant differences, the retention percentage after oral ingestion may change between different forms [49]. Following the ingestion of 1 μg of Cbl, the retention of Ado-Cbl and H-Cbl is 34% and 56%, respectively. Following the ingestion of 5 μg of Cbl, the retention of Ado-Cbl and Cn-Cbl is 13% and 20%, respectively. Following the ingestion of 25 μg of Cbl, the retention of Cn-Cbl and Ado-Cbl is 6% and 8%, respectively [50]. Updated data are not currently available."

"Supplementation is often avoided due to preconceptions and aversion to products which are thought to be artificial, or due to the myth that the shortage will manifest itself only in rare cases after many years of ceased intake, an idea also supported by some researchers [115]. Although the shortage is documented in the macrobiotic community, many feel reluctant to use supplements, fortified foods, and more generally, processed foodstuffs [116]."

"The concomitant use of more specific markers enables a more detailed diagnosis. In adult German vegetarians, Cbl deficiency was present in 58%–66% or 61%–72% of participants if both criteria HTCII/MMA or HTCII alone were adopted, respectively [84,91,93,95]."

"Although in the past it was thought that only [vegans] were at risk of vitamin deficiencies, recent studies indicate that even the [lacto and ovo and vegetarians] are at risk [125,126,127]. Herrmann et al. found that deficiency rates among LOV/LV and VN were 32% and 43%, respectively [85]. Supplementation in LOV/LV was effective in reducing deficiency rates from 68% to 31%, but the amounts were still insufficient [18]. Also the increase of MCV and RDW, associated with the lack of Cbl, leads to the increased cardiovascular risk [128,129]. Neurological manifestations of vitamin deficiency can also occur in the absence of anemia [130]."

"Supplements have been demonstrated as efficient in the restoration of Cbl blood concentration [97,138]. Currently, the official position of associations and government agencies is categorical and unequivocal: in the case of a vegetarian diet, including LOV, LV and OV, supplementation of Cbl is required [11,13]. Cbl concentration per 100 g of cow’s milk, dairy products and chicken eggs ranged from 0.5 to 0.4 μg, from 4.2 to 3.6 μg, and from 2.5 to 1.1 μg, respectively [139,140]. Taking into account the losses during cooking and the specific absorption rate, these quantities are not sufficient to ensure the daily intake in a balanced diet [141]."

"Its safety has been demonstrated through the use of an ultra-high parenteral dose of 25 mg daily for 10 days followed by 25 mg monthly for five months [150]."

"The therapeutic administration of oral Cbl has proven to be as effective as intramuscular administration [152]. This is very useful, as intramuscular administration is far more expensive and rather painful for the patient, as well as not being free from complications [153]."

"Since the crystalline form of Cbl is not bound to food proteins, the bioavailability in supplements is equal, if not superior."

"The vegetarian diet is very high in fiber, which may reduce the ability to absorb some nutrients efficiently [156]. An excess of fiber in the diet could disrupt the re-absorption of the Cbl mechanism through enterohepatic circulation, although there is no evidence to confirm that this happens in humans [157]."

"The consumption of oral doses of 1 μg, 10 μg, 50 μg, 500 μg, 1000 μg, are absorbed with an efficiency of 56%, 16%, 3%, 2%, 1.3%, respectively [151]."

"Using multivitamins can be inefficient and counterproductive for the supplementation of Cbl. The Cbl can be degraded in the presence of vitamin C and copper with the formation of inactive by-products. These compounds can inhibit the transport system interacting with transporter proteins [172,173]. Nutritional yeast fortified with Cbl is available in the USA, though its use may be less effective than supplements, in the case of deficiency [97]."

"[..]an Italian study has shown that selected types of oyster mushrooms grown in the southern areas of Italy show a wide range of concentrations of Cbl from 0.44 to 1.93 μg/100 g, as detected by ELISA immunoassay. The highest concentration was found in the species Pleurotus nebrodalis, typical of the mountain areas in central Sicily [176]. Less common mushrooms such as Craterellus cornucopioides or Cantharellus cibarius may contain 1.09–2.65 μg/100 g [177]. Shiitake mushrooms, popular among vegetarians, can contain up to 5.61 ± 3.9 μg of Cbl per 100 g of dry weight (mostly in active form), although with great variability [178]. Even in this case, although a portion of 50 g of dried shiitake could be adequate to achieve the daily requirement, it is unlikely that this will happen daily. Among the most widely used edible seaweeds, Enteromorpha sp. and Porphyra sp. (also known as nori) contain relevant amounts of Cbl ranging from 32.3 to 63.6 μg/100 g [179]. In vitro tests are promising, but there are not enough human clinical trials to consider the use of seaweed as favorable in vitamin provision [180,181]. In a clinical trial of six vegan children, the daily use of nori seaweed seemed to prevent Cbl deficiency, measured via serum Cbl [182]. In disagreement with these data, Dagnelie et al. found no positive effects in using nori seaweed and spirulina on Cbl-deficient children [183]. The Cbl content of other edible macroalgae is negligible and approximately zero [184]."

"Some fermented vegetable foods, such as sauerkraut, natto and tempeh, can have significant amounts of Cbl. It is unlikely that their daily use in Western countries represents a stable source of Cbl. The presence of Cbl in these foods depends on environmental bacteria randomly present in the fermentative microorganism pool [194]. It is very difficult to standardize the content from one product to another as they are subject to wide variation. Tempeh, for example, during the fermentation of soy beans can develop Cbl in a range between 0.7 to 8 μg per 100 g [195]. Other fermented soy foodstuff has only trace amounts of Cbl [196,197]. In sauerkraut production, the addition of Proprionibacteria sp. to cabbage may boost Cbl concentration up to 7.2 μg/100 g [198]. The use of organic fertilizer can increase the content of Cbl in spinach leaves up to 0.14 μg/100 g. However, the quantity of spinach that needs to be ingested in order to satisfy the daily requirement would be prohibitive [199]."

"According to Carmel, a single oral dose of 50 μg, 500 μg or 1000 μg will be absorbed at an amount of 1.5 μg, 9.7 μg or 13 μg, respectively [151]."

"There were no apparent substantial differences between the absorption of sublingual and oral forms [152,206]. However, oral dissolution could be critical in the secretion of the salivary R-binder and its subsequent bond. Since the Cbl would not be dissolved, about 88% could be not absorbed [54]. Since the development of a Cbl deficiency can also be observed among the LOV, the use of a supplement is necessary, regardless of the type of vegetarian diet [110]."

"If rare genetic defects of cellular trafficking and processing proteins exist, the choice of alternative forms of Cbl, such as Me-Cbl or H-Cbl could improve the effectiveness of supplementation [154,208,209,210]."

"The current data do not support the theory that vitamin deficiency needs 20–30 years to be manifested [125]."

"[..]cobalamin displays other functions, not strictly metabolic, that could be lacking when deficient. A vitamin B12 deficiency could be related to oxidative stress markers like plasma glutathione, malondialdehyde and serum total antioxidant capacity, which could contribute to a neurophysiological disturbance [220]. Furthermore, Cbl, particularly H-Cbl, can act as a detoxifying agent, removing potentially dangerous cyanid molecules from the body [212]."​

.
- Treatment of vitamin B12 deficiency–Methylcobalamine? Cyancobalamine? Hydroxocobalamin?—clearing the confusion

"In vitamin B12 deficiency, decreased MeCbl leads to the ‘folate trap’, that is, a functional deficiency of folate.4"

"Vitamin B12 has two active forms, methylcobalamin and adenosylcobalamin (AdCbl), formed as a result of two distinct metabolic cascades.1,6,7 Their metabolic fates and thereby their functions are also distinct. AdCbl is the major form in cellular tissues stored in the mitochondria. MeCbl is found in the cytosol, and it predominates in blood and in other body fluids.8"

"In vitamin B12 deficiency, decreased AdCbl leads to a decrease in the conversion of methylmalonyl-CoA to succinyl-CoA with a resultant increase in methylmalonyl-CoA, which disturbs the carbohydrate, fat, aminoacid and urea metabolism and thereby affects the synthesis of neuronal myelin.10"

I'm quoting these again to include images this time:

Spoiler: Figure 5

Mitochondrial encephalomyopathy with elevated methylmalonic acid is caused by SUCLA2 mutations

Spoiler: Methylmalonic Acidaemia

Methylmalonic Acidemia « New England Consortium of Metabolic Programs

.
"To summarize, the preferred formulation for vitamin B12 deficiency should be a combination of the active forms of vitamin B12, MeCbl and AdCbl, or HCbl[.]" "In case of the oral route, about 500–750 μg of each, MeCbl and AdCbl, would be required. A lower quantity may be required via the parenteral route. Only in the rare genetic disorders of conversion of vitamin B12 to its active coenzyme forms are the active forms to be used exclusively by the parenteral route."​

.
- Vitamin B-12 status, particularly holotranscobalamin II and methylmalonic acid concentrations, and hyperhomocysteinemia in vegetarians | The American Journal of Clinical Nutrition | Oxford Academic

↳ Vitamin B-12 status, particularly holotranscobalamin II and methylmalonic acid concentrations, and hyperhomocysteinemia in vegetarians | Oxford Academic​

For normal Vitamin B12 absorption in the terminal ileum, the vitamin must bind to salivary haptocorrin and then to “intrinsic factor”, a protein factor which is secreted by the parietal cells of the stomach. The most common reason for Vitamin B12 deficiency in humans is not dietary but a failure of intrinsic factor secretion, leading to pernicious anaemia.

I then found this study pretty interesting:
Heterologous human intrinsic factor expression from probiotic yeast Saccharomyces boulardii

 

[somuch4food]

This is so interesting because long ago I used B12 injections for sciatica. I was pregnant and could barely walk. Friends recommended a doctor who gave me B12 injections which cured the sciatica.

Through the years, if sciatica returned, I'd use B12 injections. Now, I use it twice a week. When I go too long between injections, I get foot pain...

I'm reading really interesting stuff about B12 atm. Since I'm pregnant again and borderline anemic and have some trouble with the sciatica in my right leg like last time, I'm thinking I might have a B12 deficiency. I have switched from a prenatal containing cyanocobalamin to one that contains methylcobalamin and it seems as if my body is starting to heal many ailments I have accumulated in the last few years.

I will try to ask my doctor at my next appointment.

 

[reality]

While on the topic of b12, I had a blood test done a while back and my b12 levels were super high, well out of range. I take a b complex on a occasion, but I hadn’t taken it for about a week before my blood test so it couldn’t be that.

What could be the cause of the high b12? It’s like my body is not utilising it properly maybe? Idk

 

[mangoes]

While on the topic of b12, I had a blood test done a while back and my b12 levels were super high, well out of range. I take a b complex on a occasion, but I hadn’t taken it for about a week before my blood test so it couldn’t be that.

What could be the cause of the high b12? It’s like my body is not utilising it properly maybe? Idk

How high is “super high”?
There are a few conditions that can cause elevated levels. If you’re certain it isn’t supplements and it’s elevated a lot over the range it’s worth looking further into tbh. You wanna rule out serious underlying causes.

 

[reality]

How high is “super high”?
There are a few conditions that can cause elevated levels. If you’re certain it isn’t supplements and it’s elevated a lot over the range it’s worth looking further into tbh. You wanna rule out serious underlying causes.

>300 pmol/L

I have done a 23andme test and it claims I have the MTHFR mutation (A1298C) so I dunno if that could be related?

What conditions?

 

[mangoes]

So your number was 1000pmol/L? I’m pretty sure I remember reading about how Japan raised its reference range to 1300. So by that standard you don’t have hypervitaminemia, but by your lab your result is “high” - “very high” (depending on the number itself. If it’s 1000-1300 it’s just “high”).

I’m more familiar with b12 deficiency problems but I’ve known a few people with hypervitaminemia b12 before. I wouldn’t worry too much. I don’t think it points to anything serious necessarily but there’s a significant association to a few things and can help early diagnosis. Check your liver, kidneys, FBC. It’s just worth talking to a doctor and getting some tests run

 

[Birdie]

I'm reading really interesting stuff about B12 atm. Since I'm pregnant again and borderline anemic and have some trouble with the sciatica in my right leg like last time, I'm thinking I might have a B12 deficiency. I have switched from a prenatal containing cyanocobalamin to one that contains methylcobalamin and it seems as if my body is starting to heal many ailments I have accumulated in the last few years.

I will try to ask my doctor at my next appointment.

I was living in Southern California at the time of my pregnancy related sciatica. Somebody recommend a nearby doctor who gave me the injections. I think it might be difficult to find such a doctor now. My ob/gyn didn't suggest the injections.

Am pretty sure the injections were the cyano form. I use both now. I understand that B12 can be well absorbed taken under the tongue. But, I don't trust it. The injections work for me and the oral or sublingual doses don't. Am talking about it's use for sciatica and foot pain.

The dose was 1000mcg. I think,, since that is a standard dose injected. I use 500 now, three times a week.

 

[Amazoniac]

Many factors to potentiate the toxic nature of poison A, these are related:

- Diabetes as a Cause of Clinically Significant Functional Cobalamin Deficiency
- Functional cobalamin (vitamin B12) deficiency: role of advanced age and disorders associated with increased oxidative stress
- Advanced glycation end products overload might explain intracellular cobalamin deficiency in renal dysfunction, diabetes and aging
- Vitamin B12 in Relation to Oxidative Stress: A Systematic Review

- Supraphysiological vitamin B12 serum concentrations without supplementation: the pitfalls of interpretation

- Disorders of Intracellular Cobalamin Metabolism | NCBI Bookshelf

 

[Amazoniac]

- Vitamin B12: Could It Be a Promising Immunotherapy?

"Vitamin B12 plays a crucial role in the proper functioning of immune system. Methionine synthase, which uses methylcobalamin as a cofactor, is essential for the synthesis of purines and pyrimidines in all cells, including fast-dividing immune cells. Several studies (both in man and on animal models) have reported the exact function of vitamin B12 in the immune response.

B12 deficiency leads to a low number of lymphocytes and impairs the activity of NK cells (the most important for destroying cancer cells) [35]. More specifically, CD8+ cells are decreased in patients with B12 deficiency anemia when compared to control population. Although the total number of CD4+ lymphocytes remains the same, the proportion of CD4+ is significantly elevated in such patients, and hence an abnormally high CD4/CD8 ratio is detected. A considerably suppressed NK cell activity was also noted in humans with B12 deficiency [35], as well as a decrease in the spleen NK activity was observed in rats on B12-deficient diet, although this effect was not statistically significant in the thymus or axillary nodes [36].

Intramuscular injections with B12 (under the form of methylcobalamin) in newly diagnosed B12-deficient patients completely restore the production of CD8+ T lymphocytes, the abnormally increased CD4/CD8 ratio, the CD3−CD16+ and CD16+CD57+ count (which possess strong NK cell activity), and hence the NK cells activity [35]. In contrast, serum levels of immunoglobulins are not affected by vitamin B12 deficiency or supplementation [35]. Intramuscular administration of cyanocobalamin in patients with pernicious anemia and low serum levels of vitamin B12 (three to ten times lower than reference level) increases the number of CD8+ and decreases CD4/CD8 ratio back to normal [37].

In addition, a significantly lower lymphoblastic response to Mycobacterium paratuberculosis and higher susceptibility toward gastrointestinal nematodes were reported in lambs put on B12-deficient diet, but no differences were found in white blood cell counts and antibody production against bovine herpesvirus type 1 and M. paratuberculosis [38].

An enhancing effect of methylcobalamin on the proliferative response to concanavalin A (a selective T cell mitogen) and autologous B cells was also observed in human T lymphocyte cultures in vitro [39].

Vitamin B12 could minimize the effects of protein malnutrition in the hematological or immune system—30-day addition of vitamin B12 to a low-protein diet restores white blood cell number in rats fed to protein-deficient diet [40]. All lymphocyte subpopulations are completely restored back to control levels except neutrophils and eosinophils. Rats fed a protein-deficient diet supplemented with vitamin B12 present also a normal CD4/CD8 ratio [40]. This finding is extremely important as protein malnutrition often happens in cancer patients in result of the higher demands of the tumor."​

 

[Amazoniac]

- Vitamin B12 as a regulator of bone health (@Moderator)
- Methylcobalamin: A Potential Vitamin of Pain Killer (中國)
- Decyanation of vitamin B12 by a trafficking chaperone

 

[Blossom]

- Vitamin B12 as a regulator of bone health (@Moderator)
- Methylcobalamin: A Potential Vitamin of Pain Killer (中國)
- Decyanation of vitamin B12 by a trafficking chaperone

Thank you for the fine reading sir.

 

[blabla123]

IIRC Lonsdale talks a lot about this, specifically that inactive folate and b12 accumulates in the blood when people have low metabolism.

 

[Amazoniac]

- B12 Deficiency And Hypothyroidism

The poser's highlights above were distorting. It gaved the impression that the form doesn't make a difference, but it does. Put in another way:

"One animal study compared the effects of supplementation with MeCbl versus CNCbl and showed that CNCbl urinary excretion that was 3 times higher than that of MeCbl. Although absorption in the blood of the 2 B12 forms was similar, the study found that MeCbl supplementation caused 13% more cobalamin to be stored in the liver than did CNCbl supplementation.[7]"

"Chalmers[8] reviewed the results of 3 human studies that also found lower tissue retention of B12 as a result of supplementation with CNCbl rather than OHCbl, MeCbl, or AdCbl, together with increased urinary excretion of CNCbl. The researchers concluded that the lower bioavailability of CNCbl was due to its lower efficiency in cellular uptake and metabolic activation. Other researchers are concerned about cyanide accumulation in human tissues from long-term intake of CNCbl from supplements and/or fortified foods.[2,9] Thus, it seems that the CNCbl is an inferior choice for use in nutritional supplements or injections of B12. In fact, a Lancet review has proposed the discontinuation of CNCbl because OHCbl had been made available, and owing to concerns regarding the cyanide moiety, especially for smokers.[10]"

"Another cellular study showed that the lysosomal reduction to cobalamin, when B12 is supplemented as AdCbl, was 67 times slower than the reduction of MeCbl to cobalamin. Thus, AdCbl supplementation may result in a slower synthesis of intracellular AdCbl and MeCbl compared with MeCbl supplementation.[31]"

"All forms of B12—CNCbl, MeCbl, OHCbl, and AdCbl—seem to be absorbed with similar efficiency in the blood stream but differ in overall bioavailability, as reflected by their tissue retention rates. That fact may be due to different affinities for the blood-transport binding proteins, cell receptors for B12 uptake, and intracellular enzymes involved in their conversion to intracellular cobalamin."

"Numerous studies and reviews of B12 metabolism have shown that CNCbl, MeCbl, OHCbl, and AdCbl are reduced to the core cobalamin molecule inside the cytosol. It is important to note that the ligands specific to the ingested B12 form—methyl and adenosyl—are removed during that process and not used inside cells during the conversion of cobalamin to the 2 active forms of B12 (Figure 1).[6,25–30] Activation of cobalamin occurs in very specific cellular environments; cobalamin is converted into MeCbl inside the cytosol and to AdCbl inside mitochondria. The final amounts and ratios of MeCbl and AdCbl produced do not depend on the initial form of B12 that had entered the cells.[25] However, those amounts might vary based on cell type, specific cellular conditions, and genetic polymorphisms of those metabolic pathways."

"It is clear that the form of B12 entering the body does not differentially influence the metabolite levels in any methylation reactions. However, the amount of vitamin B12 ingested at one time and its bioavailability, reflected by the portion converted to cobalamin inside cells, is relevant. Those factors can influence the extent to which 5-MTHF, available inside cells, will be used for methylation reactions and DNA synthesis.[32,33]"

"It is important to understand that the conversions to active B12 forms do not employ the methyl or adenosyl ligand from supplemental MeCbl or AdCbl, respectively. The methyl group is derived from other molecules—5-MTHF, SAM-e, or betaine—while the adenosyl group is synthesized inside cells."

"As a result, the form of ingested B12 may influence how much cobalamin is produced inside cells but not how it is converted to MeCbl, AdCbl, or various active metabolites involved in methylation reactions. Genetics may affect the activity of enzymes involved in absorption, binding to B12 blood transport or intracellular proteins and/or B12 metabolism."

"Each B12 form is chaperoned out of lysosomes into the cytosol by specific proteins and then converted to cobalamin by enzymes specific to each B12 form. Thus, it is conceivable that individuals with SNPs on those particular metabolic pathways may benefit from supplementation with the B12 forms that are metabolized on the alternate pathways, if those are SNP free." "The current review shows that claims, such as “supplemental OHCbl delivers fewer methylating metabolites than supplemental MeCbl” are not scientifically substantiated. Supplemental OHCbl may deliver more, less, or the same amount of cobalamin inside cells as other B12 forms, thus resulting in the production of higher, lower, or equal amounts of intracellular MeCbl, respectively."​

Supplementation should be safer when collagen is consumed along for the same reason that it's good to have enough glycine with methionine.

 

[Amazoniac]

- The Vitamins: Fundamental Aspects in Nutrition and Health - Gerald F. Combs and James P. McClung

Spoiler

"The term vitamin B12 is the generic descriptor for all corrinoids (compounds containing the corrin nucleus) exhibiting the biological activity of cyanocobalamin (also cobalamin). The B12 vitamers are octahedral cobalt (Co) complexes consisting of a porphyrin-like, cobalt-centered macroring (the corrin nucleus), a nucleotide, and a second Co-bound group (e.g., CH3, H2O, CN−). The corrin nucleus consists of four reduced pyrrole nuclei linked by three methylene bridges and one direct bond. The triply ionized cobalt atom (Co3+) is essential for biological activity; it can form up to six coordinate bonds and is tightly bound to the four pyrrole nitrogen atoms. The central cobalt atom can also bind a small ligand above (α-position) and a nucleotide below (β-position) the plane of the ring system. For example, its α-position ligands include cyano (CN−) (cyanocobalamin), methyl (methylcobalamin), 5′-deoxyadenosyl (adenosylcobalamin), or hydroxo (OH) (hydroxocobalamin[2]) groups. Those, and the unliganded form with a reduced cobalt center (cob(I)alamin), are found intracellularly. Other synthetic analogs with vitamin B12 activity include forms with aqua- (H2O) (aquacobalamin[3]) or nitrite (nitritocobalamin[4]) ligands."

- The tissue profile of metabolically active coenzyme forms of vitamin B12 differs in vitamin B12-depleted rats treated with hydroxo-B12 or cyano-B12

"OH-B12 and H2O-B12 are interchangeable (depending on pH), and the term OH-B12 will be used to designate both forms."​

"Cobalamins with relatively strongly bound ligands (e.g., cyano-, methyl-, and adenosylcobalamin) are less reactive and are therefore more stable in the presence of ascorbic acid."

"Vitamin B12 is very stable in crystalline form and aqueous solution. High levels of ascorbic acid have been shown to catalyze the oxidation of vitamin B12 in the presence of iron to forms that are poorly utilized."

"Vitamin B12 is the best stored of the vitamins. Under conditions of adequate intake, the vitamin accumulates to appreciable amounts in the body, mainly in the liver (∼60% of the total body stores) and muscles (∼30% of the total). Body stores vary with the intake of the vitamin but tend to be greater in older subjects [adults in comparison to fetuses?]. Hepatic concentrations approaching 2 μg/g have been reported in humans; however, a total hepatic reserve of about 1.5 mg is typical [i.e., c. 1 μg/g]. Mean total body stores of vitamin B12 in humans are in the range of 2–5 mg. The greatest concentrations of vitamin B12 occur in the pituitary gland; kidneys, heart, spleen, and brain also contain substantial amounts; in humans, these organs each contain 20–30 μg of vitamin B12. The great storage and long biological half-life (350–400 days in humans) of the vitamin provide substantial protection against periods of deprivation. The low reserve of the human infant (∼25 μg) is sufficient to meet physiological needs for about a year."

"Vitamin B12 is excreted via both renal and biliary routes at the daily rate of about 0.1–0.2% of total body reserves (in humans this is 2–5 μg/day, thus constituting the daily requirement for the vitamin).[45] Although it is found in the urine, glomerular filtration of the vitamin is minimal (<0.25 μg/day in humans), and it is thought that urinary cobalamin is derived from the tubular epithelial cells and lymph. Urinary excretion of the vitamin after a small oral dose can be used to assess vitamin B12 status; this is called the Schilling test. The biliary excretion of the vitamin is substantial, accounting in humans for the secretion into the intestine of 0.5–5 μg g/day. Most (65–75%) of this amount is reabsorbed in the ileum by IF-mediated active transport. This enterohepatic circulation constitutes a highly efficient means of conservation, with biliary vitamin B12 contributing only a small amount to the feces."

"Vitamin B12 is delivered to cells in the oxidized from, hydroxycob(III)alamin where it is reduced by thiol- and reduced flavin-dependent reduction of the cobalt center of the vitamin (to Co+) to form cob(I)amin.[42] However, the vitamin is active in metabolism only as methyl or 5-deoxyadenosyl derivatives that have either respective group attached covalently to the cobalt atom. Therefore, vitamin B12 released from holoTC in lysosomes must enter the cytoplasm to be incorporated as methylcobalamin into methionine synthase, and traverse the cytoplasm to be incorporated as adenosylcobalamin into methylmalonyl CoA mutase. Several protein chaperones are essential to this trafficking (Fig. 18.2).[43]"

Spoiler: Fig. 18.2

"The conversion to these coenzyme forms involves two different enzymatic steps:

Methylcobalamin—Methylation of the vitamin is catalyzed by the cytosolic enzyme 5-methyl-FH4:homocysteine methyltransferase. This renders the vitamin, as methylcobalamin, a carrier for the single-C unit used in the regeneration of methionine (MET) from homocysteine (Hcy). Methylcobalamin is also produced by recharging the reduced vitamin (Co+1) with a methyl group transferred from 5-methyl FH4. This cycling risks the occasional oxidation of cobalamin–cobalt (to Co+2), in which case it is reduced back to Co+1 by the enzyme methionine synthase reductase.

Adenosylcobalamin—Adenosylation of the vitamin occurs in the mitochondrial due to the action of vitamin B12 coenzyme synthetase, which catalyzes the reaction of cob(II)amin with a deoxyadenosyl moiety derived from ATP. This step depends on the entry of hydroxycobalamin into the mitochondria and its subsequent reduction in sequential, one electron steps involving NADH- and NADPH-linked aquacobalamin reductases[44] to yield cob(II)alamin."​

The interaction between methylfolate and homocysteine is rarely detail'd:

- Insights into the reactivation of cobalamin-dependent methionine synthase

Cobalamin-dependent methionine synthase (MetH) is a modular protein that catalyzes the transfer of a methyl group from methyltetrahydrofolate to homocysteine to produce methionine and tetrahydrofolate. The cobalamin cofactor, which serves as both acceptor and donor of the methyl group, is oxidized once every ≈2,000 catalytic cycles and must be reactivated by the uptake of an electron from reduced flavodoxin and a methyl group from S-adenosyl-L-methionine (AdoMet). Previous structures of a C-terminal fragment of MetH (MetH[CT]) revealed a reactivation conformation that juxtaposes the cobalamin- and AdoMet-binding domains. Here we describe 2 structures of a disulfide stabilized MetH[CT] ([s-s]MetH[CT]) that offer further insight into the reactivation of MetH. The structure of [s-s]MetH[CT] with cob(II)alamin and S-adenosyl-L-homocysteine represents the enzyme in the reactivation step preceding electron transfer from flavodoxin. The structure supports earlier suggestions that the enzyme acts to lower the reduction potential of the Co(II)/Co(I) couple by elongating the bond between the cobalt and its upper axial water ligand, effectively making the cobalt 4-coordinate, and illuminates the role of Tyr-1139 in the stabilization of this 4-coordinate state. The structure of [s-s]MetH[CT] with aquocobalamin may represent a transient state at the end of reactivation as the newly remethylated 5-coordinate methylcobalamin returns to the 6-coordinate state, triggering the rearrangement to a catalytic conformation.

Spoiler

 

[Amazoniac]

- Magnesium, Vitamin D, B12 Combo Strikingly Therapeutic For COVID-19
⬑ [8] Vitamin B12 as a Modulator of Gut Microbial Ecology

Spoiler

"[..]early studies emphasized the requirement for increased dietary vitamins K, B1 (thiamin), B6 (pyridoxine), B7 (biotin), B9 (folic acid), and B12 (cobalamin) for the health of germfree animals (Ikeda et al., 1979; Sumi et al., 1977; Wostmann, 1981; Wostmann and Knight, 1965)."

"[..]human gut microbes are likely to present direct competition with their host for cobalamin. The great majority of human gut microbial species are predicted to require exogenous corrinoids ['related cofactors'] (Degnan et al., 2014). Notably, individuals with high bacterial loads in their small intestines tend to have low cobalamin status (Albert et al., 1980; Brandt et al., 1977; Murphy et al., 1986), possibly due to either competition for cobalamin between the host and microbes, or an overabundance of corrinoids other than cobalamin."

"Based on recent studies of the role of corrinoids in the human gut, we propose that targeted manipulations of the gut microbiota could be achieved by altering the levels of specific corrinoids. This hypothesis is based on the following observations. First, over 80% of sequenced human gut bacteria are predicted to use corrinoids, but less than 25% have the genetic capacity to synthesize these molecules (Degnan et al., 2014); second, human fecal samples have been found to contain up to eight distinct corrinoids (Allen and Stabler, 2008). Third, only a fraction of the corrinoids available in a microbial community can be used by a given organism, because corrinoid-dependent enzymes have native specificity for their preferred cofactors (Keller et al., 2013; Mok and Taga, 2013; Yi et al., 2012). Fourth, corrinoids other than cobalamin are poorly recognized by human intrinsic factor, the key protein required for transport of cobalamin from the lumen of the small intestine. Finally, corrinoids are synthesized exclusively by bacteria and archaea, unlike many other vitamins that are also prevalent in plant-based dietary components (Roth et al., 1996). Thus, because different bacteria require distinct groups of corrinoids, we hypothesize that microbial communities can be manipulated by altering the levels of particular corrinoids."

"An analysis of the corrinoid composition of fecal samples of 20 individuals by Allen and Stabler (2008) revealed differences in both the total corrinoid levels and the proportion of each corrinoid (Figure 3B). It still remains to be tested whether these differences are correlated with distinct microbial signatures in these communities. For example, a corrinoid found almost exclusively in methanogens, 5-hydroxybenzimidazolylcobamide ([5-OHBza]Cba) (Pol et al., 1982; Ryzhkova and Briukhanov, 2009), was detected in only 30% of the samples analyzed. It would be interesting to test whether the presence or amount of this corrinoid correlates with the abundance or metabolic activity of methanogenic archaea, which are also found in approximately 30% of individuals (Hansen et al., 2011)."

"Allen and Stabler’s landmark study of corrinoids in human fecal samples also revealed the effect of high doses of cobalamin on the corrinoid composition of the gut (Allen and Stabler, 2008). Individuals who ingested 1 to 2 mg cobalamin per day (nearly 1,000-fold higher than the recommended daily allowance in the USA) not only had higher levels of this vitamin in the feces, as would be expected if some of the supplement was not absorbed in the small intestine, but also had high levels of nearly all other corrinoids (Figure 3B). Furthermore, when examined over time in a single individual, the increase in corrinoid levels was found to be transient, as each corrinoid returned to the original level after only 10 days. The increase in total corrinoid levels following cobalamin supplementation is indicative of corrinoid remodeling, in which the lower ligand of a corrinoid is removed and another is attached (Gray and Escalante-Semerena, 2009). Corrinoid remodeling has been observed in archaea and bacteria grown in pure culture and is thought to be a mechanism of obtaining specific corrinoids needed for metabolism (Escalante-Semerena, 2007; Gray and Escalante-Semerena, 2009; Yi et al., 2012). The observation that corrinoid remodeling allows the gut microbiota to maintain a stable corrinoid composition points to the robustness of this community and an important challenge in modulating corrinoid levels by supplementation with a biologically active corrinoid. Alternative approaches could be to provide synthetic corrinoid analogs that are not recognized by the remodeling machinery, or lower ligand bases to be incorporated to form desired corrinoids (known as guided biosynthesis). It would be interesting to examine the microbial composition and gene expression profiles following cobalamin supplementation as a means to understand the short-term and long-term effects of perturbations of corrinoid metabolism."

 

[Recoen]

I take 76ug adenosylcobalamin liquid metabolics brand in 500mL of water (with other Bs) spread throughout the day. I don’t have anemia (Hg=14.7) but it helps my lower leg bruising. Adeno is used after biotin in TCA for succinyl coa. And of course can be used to make methylcobalamin.

 

[magnesiumania]

B12 is a photoreceptor. Strong UV light can correct a deficiency.

 

[Recoen]

B12 is a photoreceptor. Strong UV light can correct a deficiency.

Isn’t this assuming you have the bacteria capable of synthesizing it? And they “share” what they make with you?

 

[magnesiumania]

Yes.