Physicochemical Characteristics, Biological Functions and Deficiency

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Vol. 14, No.2 - July- Dec. 2011 J. Baqai Med. Univ. Physicochemical Characteristics, Biological Functions and Deficiency of Cobalamins Saima Zahid, Kiran Qadeer and Iqbal Ahmad ABSTRACT Cobalamins are complex organometallic compounds of biological interest present in animal food products including meat, eggs and milk. The clinically important cobalamins, i. e. cyanocobalamin (vitamin Bl2), hydroxocobalamin and methylcobalamin exist as coenzymes in biological system and are involved in several biochemical functions. The deficiency of vitamin B12 occurs mainly due to its malabsorption and results in pernicious anemia. This disease is age related and is associated with the destruction of parietal cells in the stomach. Clinical studies with high dose supplementation of cobalamins suggest a strong correlation between the duration of cognitive symptoms of the disease and the therapy. Neural tube defects and other birth defects have also been reported with cobalamin deficiency.

INTRODUCTION methylcobalam in , a den osylcobalamin and Vitamin B 12 and its derivatives remain the center of hydroxocobalamin. Methylcobalamin and interest for pharmacists and chemists because of being hydroxocobalamin are the dominant forms of an extraordinary group member of organometallic cobalamins that are present in diary food items while complexes. They are classified as cobalamins, a class adenosylcobalamin and hydroxocobalamin are present 9 of octahedral Co(III) complexes. Vitamin B12 was in meat • 2 first discovered in 19481, , later named as 4 cyanocobalamin3 and was first syn~hesized in 1973 . CHEMICAL STRUCTURE Cobalamins are exclusively synthesized by bacteria Cobalamins possess a complex strucfure based on 5 6 and primarily found in animal products • . corrin ring system. Four reduced pyrrole rings are The richest sources of cobalamins are animal organs linked together to form a corrin nucleus which is (specially liver and kidney) and meat7. These are found chelated by four pyrrole nitrogens. All compounds in those tissues which require the vitamin for critical that contain such a ring system are termed corrinoids. function in cellular division and growth. Some animal This macrocyclic ring is coordinated centrally to a tissues have the ability to store the vitamin in such cobalt atom (Fig.1). amounts which are sufficient enough to meet the requirements of the organisms for long periods of deprivation. Fish, shell fish, mushrooms, eggs, milk and bacterially fermented foods are enriched with vitamin B12. Plant derived foods are devoid of B12 6 7 unless they are contaminated • . Some algae also contain cobalamins but such analogues are ineffective7 such as edible cyanobacteria-(Spirulina, Apahnizomenon, Nostoc) and are often cited as vitamin B12. However, they are enriched with large amounts of pseudovitamin B12 (7-adeninyl cyanocobamide) which is biologically inactive and may antagonize the 6 8 utilization of vitamin Bl2 • . The principal vitamer cobalamins in food are Vol. 14, No.2 - July- Dec. 2011 J. Baqai Med. Univ.

The molecule can be divided into two halves, a planar Cobalamins are required by cellular enzyme, as group and a nucleotide which are set at right angle to cofactor in either the adenosylcobalamin or the each other. Corrin ring constitutes the planar group methylcobalamin form. Methylcobalamin is required while nucleotide consist of· 6 dimethylbenzimedazole for the remethylation of homocysteine to methionine 7 20 and a phosphorylated sugar (ribose 3-phosphate)3. catalyzed by methionine synthase • . Methionine The fifth ligand of the cobalt may be occupied synthases are large monomeric zinc metalloproteins covalently by different anionic groups giving rise to and comprise of the three domains, a catalytic domain 4 10 various forms of cobalamins • . Th~ ligand of the which contain the binding site for anionic group (X) can be one of the following types. methyltetrahydrofolate and homocysteine, a B12 CN - cyanocobalamin domain where B 12 cofactor binds and an accessory OH - hydroxocobalamin protein domainl0. In this reaction, H2O - aquacobalamin methyltetrahydrofolate is involved as an intermediate 7 NO2 - nitritocobalamin acceptor of the methyl group • The cob(l)amin cofactor SO3 - sulfitocobalamin is methylated by 5- methyltetrahydrofolate generating CH3 - methylcobalamin enzyme bound methylcob(III)amin and releasing 5-deoxyadenosyl - adenosylcobalamin tetrahydrofolate. The methyl group is transferred by In cyanocoabalamin and the naturally occurring methlcob(IIl)amin to homocystein to generate hydroxocobalamin forms the cobalt atom is methionine and regenerate the enzyme bound 10 trivalent Cob(III)amin, the most oxidized form . cob(I)amin cofactor. Occasionally this cofactor is oxidized to the non-functional cob(ll)amin form during PHYSICOCHEMICAL CHARACTERISTICS catalysis. The enzyme is reactivated by methionine The physicochemical characteristics of clinically synthase reductase that catalyzes the important cobalamins are given in Table 1. adenosylmethioine and NADPHdependent reductive methylation of enzyme bound cob(Il)amin 10 ABSORPTION , TRANSPORTATION AND to methylcob(IIl)amin . In all cobalamin deficiency METABOLISM OF VITAMIN B12 states methionine synthesis is impaired and Vitamin B12 is present in protein bounded forms in homocysteine can accumulate. foods. Dietary B12 is released.from the protein complex Further the methionine synthesis reaction provides in the acidic environment of stomach by the action tetrahydrofolic acid (THF), which is an essential form 21 of pepsin. The released B12 then binds to salivary R for other folate dependent reactions . binders. This complex is then hydrolyzed by proteases The adensoylcoabalmin present in mitochondria is in the small intestine. The free B 12 is available to bind required as a coenzyme for methyl-malonyl - Co A with the intrinsic factor (gastric glycoprotein). The mutase. This enzyme catalyzes the conversion of IFB12 complex then binds to IF receptor. All forms methylmalonyl-Co A to succinyl Co-A21 which then 22 of vitamin B12 are absorbed by IF dependent enters to Kreb's cycle . mechanism 10. The passive diffusion is another mean of B 12 absorption occurring equally through the Other Functions absorption surface of gastrointestinal tract. Cobalamins may function to modulate the oxidative Approximately 1-2% of the oral dose of vitamin B12 stress responses, including inflammatory response. 6 9 is absorbed by this mechanism • . Inflammatory diseases are associated with increased 23 blood levels of transcobalamin . Cobalamins may BIOLOGICAL FUNCTIONS OF COBALAMINS function as antioxidant which could result from Metabolic Function combination of direct or indn:ect effects of stimulation Vol. 14, No.2 • July-Dec. 2011 J . Baqai Med. Univ.

2 24 methionine synthase activity2 • . Direct reaction with deficiency of folate which is required by other f

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