Kidneys cobalamins

Strict vegetarian diet or after diseases affecting cobalamin absorption. The main effects of vitamin deficiency are pernicious anemia, macrocytosis, and neurological problems. A particularity of this vitamin is that it can be stored especially in the liver and kidneys. 

The loss of a methyl group from AdoMet in each of the reactions yields S-ad-enosylhomocysteine (AdoHcy) and this is subsequently hydrolysed to adenosine and Hey by AdoHcy-hydrolase. Hey sits at a metabolic branch point and can be remethylated to methionine by way of two reactions. One is the 5-methyltetrahydrofo-late dependent reaction catalysed by methionine synthase, which itself is reductively methylated by cobalamin (vitamin B12) and AdoMet, requiring methionine synthase reductase. 5-Methyltetrahydrofolate is generated from 5,10-methylenetetrahydrofo-late (MTHF) by MTHF reductase. The second remethylation reaction is catalysed by betaine methyltransferase, which is restricted to the liver, kidney and brain, while methionine synthase is widely distributed. 

Measurement of blood tHcy is usually performed for one of three reasons (1) to screen for inborn errors of methionine metabolism (2) as an adjunctive test for cobalamin deficiency (3) to aid in the prediction of cardiovascular risk. Hyperhomocysteinemia, defined as an elevated level of tHcy in blood, can be caused by dietary factors such as a deficiency of B vitamins, genetic abnormalities of enzymes involved in homocysteine metabolism, or kidney disease. All of the major metabolic pathways involved in homocysteine metabolism (the methionine cycle, the transsulfuration pathway, and the folate cycle) are active in the kidney. It is not known, however, whether elevation of plasma tHcy in patients with kidney disease is caused by decreased elimination of homocysteine in the kidneys or by an effect of kidney disease on homocysteine metabolism in other tissues. Additional factors that also influence plasma levels of tHcy include diabetes, age, sex, lifestyle, and thyroid disease (Table 21-1). 

Few natural sources are rich in vitamin B12. However, only very small amounts are required in the diet. Good sources are lean meat, liver, kidney, fish, shellfish, and milk (Table 9-23). In milk, the vitamin occurs as cobalamine bound to protein. 

Cobalamin is not significantly metabolised and passes into the bile (there is enterohepatic circulation which can be interrupted by intestinal disease and hastens the onset of clinical deficiency), and is excreted via the kidney. Body stores amount to about 5 mg (mainly in the liver) and are sufficient for 2-4 years if absorption ceases. 

Homocysteine is metabolized in the liver, kidney, small intestine and pancreas also by the transsulfuration pathway [1,3,89]. It is condensed with serine to form cystathione in an irreversible reaction catalyzed by a vitamin B6-dependent enzyme, cystathionine-synthase. Cystathione is hydrolyzed to cysteine that can be incorporated into glutathione or further metabolized to sulfate and taurine [1,3,89]. The transsulfuration pathway enzymes are pyridoxal-5-phosphate dependent [3,91]. This co-enzyme is the active form of pyridoxine. So, either folates, cobalamin, and pyridoxine are essential to keep normal homocysteine metabolism. The former two are coenzymes for the methylation pathway, the last one is coenzyme for the transsulfuration pathway [ 1,3,89,91 ]. 

The whole-body content of Co in an adult of 70 kg is estimated to be 1.1 mg, 85% of which is incoq)orated into cobalamines or linked with low molecular weight proteins [14]. The remaining 15% is in the skeleton. The total amount of vitamin B12 in the body is 2-5 mg (i.e., 0.09-0.22 mg of Co the vitamin containing 4.34% of Co) [18,21]. In humans and animals, Co does not accumulate in a target organ. Nevertheless in humans the highest levels are found in liver and kidney [17]. 

The kidney plays an important role in regulating cobalamin flux. The lower the glomerular filtration rate (GFR), the more circulating holoTC is required to... 

Vitamin B12 must be converted into its coenzyme forms, adenosylcobalamin and methylcobalamin, in the cell. These coenzymes function as cofactors of methylmalonyl-CoA mutase and methionine synthase, respectively. Chronic kidney disease (CKD) may affect the conversion from vitamin B12 to the coenzyme forms. This section describes the intracellular metabolism of cyanocobalamin, which is included in many dietary supplements, in particular, referring to a recently discovered trafficking chaperone called methylmalonic aciduria cdlC type with homocystinuria (MMACHC). Cyanocobalamin is first converted to cob(II)alamin, which has no cyanogen group on the ligand occupying the upper axial position of the cobalamin structure. Cob(II)alamin is further reduced to cob(I)alamin, which can function as a coenzyme in the body. 

Pure nutritional cobalamin deficiency being extremely rare, most other causes of cobalamin deficiency require lifelong treatment with parenteral, mainly intramuscular, administration of cobalamin. Both cyano- and hydroxocobalamin are being used for this purpose. Unbound cobalamin in the circulation cannot be retained by the kidney, and is excreted. As hydroxocobalamin binds more strongly to plasma proteins other than the specific cobalamin binders, it is better retained by the body and thus more effective. After replenishment of the cobalamin stores by about five doses of at least 250 p-g hydroxocobalamin on alternate days, cobalamin homeostasis can be maintained by bimonthly injections of 1000 pg cobalamin. 

Animals, plants, and fungi are incapable of producing cobalamin it is the only vitamin that is exclusively produced hy microorganisms, particularly by anaerobes (Roth et al. 1996 Martens et al. 2002 Smith et al. 2007). Furthermore, biochemical and genomic data indicate that only a few bacteria and archaea possess the abOity to produce this vitamin (Roth et al. 1996 Rodionov et al. 2003). Adult ruminant animals and strict vegetarians can obtain the vitamin in specialized bacteria present in the rumen. Humans do not have such microbiota in their small intestine and must absorb the co-enzyme from natural sources such as animal meats (especially liver and kidney), fish, eggs, and pharmaceutical products (Herbert 1996). 

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