Liver cobalamins

It soon became apparent that the biologically active forms of Vitamin Bj.2 contained the unique Co—C-a-bond, and the instability of these covalent compounds to visible light facilitated observations on the occurrence of functional corrinoids in a number of enzymes. Deoxyadenosyl-cobalamin was found to be the most abundant corrinoid in bacteria (24) and in mammalian liver (25). Methylcobalamin was found in Escherichia coli (26), calf liver and human blood plasma (27), and also in a number of Clostridia (28). 

Vitamin Bn deficiency Deficiency, although rare, results in two serious problems megaloblastic anaemia (which is identical to that caused by folate deficiency) and a specific neuropathy called Bi2-associated neuropathy or cobalamin-deficiency-associated neuropathy (previously called, subacute combined degeneration of the cord). A normal healthy adult can survive more than a decade without dietary vitamin B12 without any signs of deficiency since it is synthesised by microorganisms in the colon and then absorbed. However, pernicious anaemia develops fairly rapidly in patients who have a defective vitamin B12 absorption system due to a lack of intrinsic factor. It results in death in 3 days. Minot and Murphy discovered that giving patients liver, which contains the intrinsic factor, and which is lightly cooked to avoid denaturation, cured the anaemia. For this discovery they were awarded the Nobel Prize in Medicine in 1934. 

Vitamin B12 (cobalamine) is one of the most complex low-molecular-weight substances occurring in nature. The core of the molecule consists of a tetrapyrrol system (corrin), with cobalt as the central atom (see p. 108). The vitamin is exclusively synthesized by microorganisms. It is abundant in liver, meat, eggs, and milk, but not in plant products. As the intestinal flora synthesize vitamin B12, strict vegetarians usually also have an adequate supply of the vitamin. 

Cobalamine can only be resorbed in the small intestine when the gastric mucosa secretes what is known as intrinsic factor—a glycoprotein that binds cobalamine (the extrinsic factor) and thereby protects it from degradation. In the blood, the vitamin is bound to a special protein known as trans-cobalamin. The liver is able to store vitamin Bi2 in amounts suf cient to last for several months. Vitamin B12 deficiency is usually due to an absence of intrinsic factor and the resulting resorption disturbance. This leads to a disturbance in blood formation known as pernicious anemia. 

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. 

Vitamin B12 exists as hydroxocobalamin, adeno-sylcobalamin and cyanocobalamin. Cobalamins are found exclusively in food ingredients of animal origin like meat, liver and to a lesser degree in dairy products. Vitamin B12 is absorbed in the distal ileum under the influence of the glycoprotein intrinsic... 

Fig. 1. Folate-cobalamin interaction in the synthesis of purines and pyrimidines and, therefore, of DNA. (1) In gastrointestinal mucosa cells (2) in the liver (3) in peripheral tissues. C, cobalamine DAC, desoxyadenosylcobalamine HC, hydroxy cobalamine MC, methylcobalamine F, folic acid MTHF, methyltetrahydrofolic acid THF, tetrahydrofolic acid DHF, dihydrofolic acid dUMP, deoxyuridinemonophosphate dTMP, deoxythymidine-monophosphate. (Adapted from Far-...

Vitamin Bjj (8.50, cobalamin) is an extremely complex molecule consisting of a corrin ring system similar to heme. The central metal atom is cobalt, coordinated with a ribofuranosyl-dimethylbenzimidazole. Vitamin Bjj occurs in liver, but is also produced by many bacteria and is therefore obtained commercially by fermentation. The vitamin is a catalyst for the rearrangement of methylmalonyl-CoA to the succinyl derivative in the degradation of some amino acids and the oxidation of fatty acids with an odd number of carbon atoms. It is also necessary for the methylation of homocysteine to methionine. 

Vitamin B12 consists of a porphyrin-like ring with a central cobalt atom attached to a nucleotide. Various organic groups may be covalently bound to the cobalt atom, forming different cobalamins. Deoxyadenosylcobalamin and methylcobalamin are the active forms of the vitamin in humans. Cyanocobalamin and hydroxocobalamin (both available for therapeutic use) and other cobalamins found in food sources are converted to the active forms. The ultimate source of vitamin Bi2 is from microbial synthesis the vitamin is not synthesized by animals or plants. The chief dietary source of vitamin Bi2 is microbially derived vitamin B12 in meat (especially liver), eggs, and dairy products. Vitamin Bi2 is sometimes called extrinsic factor to differentiate it from intrinsic factor, a protein normally secreted by the stomach that is required for gastrointestinal uptake of dietary vitamin B12. 

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. 

Vitamins are chemically unrelated organic compounds that cannot be synthesized by humans and, therefore, must must be supplied by the diet. Nine vitamins (folic acid, cobalamin, ascorbic acid, pyridoxine, thiamine, niacin, riboflavin, biotin, and pantothenic acid) are classified as water-soluble, whereas four vitamins (vitamins A, D, K, and E) are termed fat-soluble (Figure 28.1). Vitamins are required to perform specific cellular functions, for example, many of the water-soluble vitamins are precursors of coenzymes for the enzymes of intermediary metabolism. In contrast to the water-soluble vitamins, only one fat soluble vitamin (vitamin K) has a coenzyme function. These vitamins are released, absorbed, and transported with the fat of the diet. They are not readily excreted in the urine, and significant quantities are stored in Die liver and adipose tissue. In fact, consumption of vitamins A and D in exoess of the recommended dietary allowances can lead to accumulation of toxic quantities of these compounds. 

Vitamin B12 is synthesized only by microorganisms it is not present in plants. Animals obtain the vitamin preformed from their natural bacterial flora or by eating foods derived from other animals. Cobalamin is present in appreciable amounts in liver, whole milk, eggs, oysters, fresh shrimp, pork, and chicken. 

Cobalt must be supplied in the diet in its physiologically active form, vitamin B12. GI absorption of cobalt is about 25%, with wide individual variation excretion occurs mainly via the urine. The major part is excreted within days and the rest has a biological half-life of about two years. Originally, the therapy for pernicious anemia was to have patients eat large amounts of liver. The most reliable treatment now is monthly injections of cobalamin. 

Vitamin B12, cobalamin or cyanocobaltamin, C63H88CoN14Oi4P, has the most complicated structure of the B vitamins. It contains one atom of cobalt in its molecule. It is required in minute amounts but without it the manufacture of proteins and red blood cells is affected. A diet which is deficient in liver, eggs, meat, fish or milk can lead to pernicious anaemia. Vegetarians are often advised to take vitamin B12 supplements. 

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 ]. 

Vitamin B12 is stable to temperatures up to 250°C (482°F) in acidic or neutral solutions. Dietary B12 deficiency is rare among meat eaters but not in strict vegetarians. The average total body content of vitamin B12 is about 2.5 mg, most of which is in the liver (1 /u,g of Bi2 per gram of hepatic tissue). There is extensive reutilization of cobalamin and an active enterohepatic circulation. The principal disease caused by vitamin B12 deficiency is megaloblastic anemia. Deficiency also causes neurological abnormalities that become irreversible if allowed to persist. 

The cobalamins are excreted in urine, bile, and feces. Intact cobalamin molecules are the predominant forms in urine. Urinary excretion is highly variable, but it averages 150 ng/d and is somewhat higher in smokers than nonsmokers. The principal excretory route is bile. Cobalamins destined for biliary excretion may be transported to the liver by TCI and TCIII. The liver is the only tissue that takes up the TCI-cobalamin complex. 

Dietary cobalamin is absorbed from animal food sources by a multistage process shown in Figure 42-2. Cobalamin absorption requires the presence of a protein (the intrinsic factor, IF) secreted from the parietal cells of the stomach to bind cobalamin and aid in its absorption in the ileum. The protein is released into the ileum while the cobalamin is transported to the blood stream where it binds specialized serum proteins, the transcobalamins (TC), which transport it to other tissues such as liver where cobalamin can be stored (usually several milligrams are present in liver). In the absence of the intrinsic factor... 

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