A. History. In 1926, two American physicians, George Minot and George William Murphy discovered that patients suffering from pernicious anemia could be cured by feeding them with about half a pound of liver a day. This landmark in medicine brought them Nobel Prize in 1934. In 1929, Castle suggested that gastric juice contained a factor (intrinsic factor) that, together with a factor present in the food (extrinsic factor), is responsible for the cure of pernicious anemia.
This anti-pernicious anemia factor (APA factor) was, later, isolated in crystalline form in 1948 independently by E. Lester Smith in England and by Edward Rickes and Karl Folkers in the United States. It was then named as vitamin B12 or cyanocobalamin. It is the last B-vitamin to be isolated and is also known as Factor X or L.L.D. factor. The coenzyme form of this vitamin (deoxyadenosyl cobalamin or cobamide coenzyme) was first isolated by Barker of California. Coenzyme B12 has been called a “biologic Grignard reagent”.
This anti-pernicious anemia factor (APA factor) was, later, isolated in crystalline form in 1948 independently by E. Lester Smith in England and by Edward Rickes and Karl Folkers in the United States. It was then named as vitamin B12 or cyanocobalamin. It is the last B-vitamin to be isolated and is also known as Factor X or L.L.D. factor. The coenzyme form of this vitamin (deoxyadenosyl cobalamin or cobamide coenzyme) was first isolated by Barker of California. Coenzyme B12 has been called a “biologic Grignard reagent”.B. Occurrence. Vitamin B12 has been found only in animals ; the chief source is liver, although it is also present in milk, meat, eggs, fish, oysters and clams
. Animal tissues contain it in varying amounts as shown in Table.
Under certain dietary conditions, vitamin B12 may be synthesized by the intestinal microorganisms. In general, cyanocobalamin is not present in plant foods except in Spirulina, a blue-green alga. However, it occurs in foods bound to proteins and is apparently split off by proteolytic enzymes.
Animals and plants are unable to synthesize this vitamin. Cyanocobalamin is unique in that it appears to be synthesized only by microorganisms especially anaerobic bacteria. However, a process of producing vitamin B12 from waste products has been developed, in 1977, by the department of Chemical Engineering of the Indian Institute of Technology, Chennai.
C. Structure. The structure of vitamin B12 of the most complex known, has been established, in 1957, by Dorothy Crowfoot Hodgkin (Nobel Laureate, 1964). Cyanocobalamin (C63H88O14N14 P Co) is a pigment alike to the tetrapyrrole ring structure of the porphyrins, e.g., chlorophyll and haem. A unique feature of this vitamin (and other related compounds) is the
presence, in its molecule, of an atom of a heavy metal cobalt in the trivalent state. No other cobaltcontaining organic compound has been found in nature. The cobalt atom is centrally-situated andis surrounded by a macrocyclic structure of 4 reduced pyrrole rings (A, B, C and D) collectively called as corrin. It may be noted from the structural formula that the 6 coordinate valences of the cobalt atom (Co2+ )are satisfied by the 4 nitrogens of the reduced tetrapyrrole, a nitrogen atom of 5, 6-dimethylbenzimidazole and a cyanide ion. Two of the pyrrole rings, namely A and D, are directly linked to each other and the corrin has lower degree of unsaturation with only 6 double bonds. The other two pyrrole rings, namely B and C, are joined through a single methene carbon. Another distinct feature of the vitamin B12 molecule is the presence of a loop of the isopropanol, phosphate, ribose and 5,6-dimethyl-benzimidazole in that order, the end of the loop being attached to the central cobalt atom. Many compounds with vitamin B12 activity have been isolated from natural sources. Cyanocobalamin is the most common form and is sometimes also written as vitamin B12a. In other forms, cyanide ion is replaced by other ions, e.g., by hydroxyl ion in hydroxocobalamin (also designated as vitamin B12b), by nitrite ion in nitrocobalamin (also designated as vitamin B12c) etc. The latter two, B12b and B12c can be converted to vitamin B12a by treatment with cyanide.The structure of vitamin B12 coenzyme ( = 5′-deoxyadenosyl cobalamin) is similar to that of cobalamin except that here the CN group is replaced by adenosine and the linking with cobalt atom taking place at 5′ carbon atom of the ribose of adenosine. Vitamin B12 coenzyme is the only known example of a carbon-metal bond in a biomolecule.is surrounded by a macrocyclic structure of 4 reduced pyrrole rings (A, B, C and D) collectively called as corrin. It may be noted from the structural formula that the 6 coordinate valences of the cobalt atom (Co2+ )are satisfied by the 4 nitrogens of the reduced tetrapyrrole, a nitrogen atom of 5, 6-dimethylbenzimidazole and a cyanide ion. Two of the pyrrole rings, namely A and D, are directly linked to each other and the corrin has lower degree of unsaturation with only 6 double bonds. The other two pyrrole rings, namely B and C, are joined through a single methene carbon. Another distinct feature of the vitamin B12 molecule is the presence of a loop of the isopropanol, phosphate, ribose and 5,6-dimethyl-benzimidazole in that order, the end of the loop being attached to the central cobalt atom. Many compounds with vitamin B12 activity have been isolated from natural sources. Cyanocobalamin is the most common form and is sometimes also written as vitamin B12a. In other forms, cyanide ion is replaced by other ions, e.g., by hydroxyl ion in hydroxocobalamin (also designated as vitamin B12b), by nitrite ion in nitrocobalamin (also designated as vitamin B12c) etc.The latter two, B12b and B12c can be converted to vitamin B12a by treatment with cyanide.The structure of vitamin B12 coenzyme ( = 5′-deoxyadenosyl cobalamin) is similar to that ofcobalamin except that here the CN group is replaced by adenosine and the linking with cobalt atom taking place at 5′ carbon atom of the ribose of adenosine . Vitamin B12 coenzyme is the only known example of a carbon-metal bond in a biomolecule.
D. Properties. Vitamin B12 (molecular weight, ca 1,500) is a deep red crystalline substance.It is soluble in water, alcohol and acetone but not in chloroform. It is levorotatory. It is stable to heat in neutral solutions but is destroyed by heat in acidic or alkaline solutions.
(d) Dismutation of vicinal diols : Coenzyme 12 also catalyzes dismutation of vicinal diols to the corresponding aldehydes, e.g., propane-1,2-diol into propionaldehyde. Vitamin B12 is also needed for the biosynthesis of methyl groups from 1-carbon precursors and for the synthesis of thymidine and other deoxyribosides. It also functions in protein synthesis and in the activation of SH enzymes. Cyanocobalamin also affects myelin formation.
F. Deficiency: A nutritional deficiency of this vitamin is usually not observed on account of its ubiquitous ( = widespread) nature in foodstuffs. Thus, most cases of deficiency stem from failure to absorb the vitamin. However, deficiency may be observed in individuals who abstain from all animal products including milk and eggs, i.e., those who are strict vegetarians.The rare disease juvenile (or congenital) pernicious anemia springs up due to an inability to secrete gastric intrinsic factors. The symptoms of this disease become prominent at 9 months to 10 years of age. As the anemia becomes severe, irritability, anorexia and listlessness occur. The tongue is smooth, red and painful. Neurologic symptoms include ataxia, paresthesias, hyporeflexia, clonus, Babinski responses and coma. Consanguinity is common in parents of affected children and suggests Mendelian recessive inheritance. The juvenile disease differs from the typical disease in adults in that the stomach secretes acid normally and is histologically normal.
This typical deficiency disease, adult pernicious anemia ( = anemia caused by failure of erythrocyte formation), is characterized by R.B.Cs. becoming abnormally large and fewer in number (1–3 million per cubic millimeter instead of the normal 4–5 million). The patient weakens, loses its weight and the nervous system is also gradually affected because there occurs demyelinization of the large nerve fibres of the spinal cord. All these changes ultimately lead to death.
. Animal tissues contain it in varying amounts as shown in Table.Under certain dietary conditions, vitamin B12 may be synthesized by the intestinal microorganisms. In general, cyanocobalamin is not present in plant foods except in Spirulina, a blue-green alga. However, it occurs in foods bound to proteins and is apparently split off by proteolytic enzymes.
Animals and plants are unable to synthesize this vitamin. Cyanocobalamin is unique in that it appears to be synthesized only by microorganisms especially anaerobic bacteria. However, a process of producing vitamin B12 from waste products has been developed, in 1977, by the department of Chemical Engineering of the Indian Institute of Technology, Chennai.
C. Structure. The structure of vitamin B12 of the most complex known, has been established, in 1957, by Dorothy Crowfoot Hodgkin (Nobel Laureate, 1964). Cyanocobalamin (C63H88O14N14 P Co) is a pigment alike to the tetrapyrrole ring structure of the porphyrins, e.g., chlorophyll and haem. A unique feature of this vitamin (and other related compounds) is the
presence, in its molecule, of an atom of a heavy metal cobalt in the trivalent state. No other cobaltcontaining organic compound has been found in nature. The cobalt atom is centrally-situated andis surrounded by a macrocyclic structure of 4 reduced pyrrole rings (A, B, C and D) collectively called as corrin. It may be noted from the structural formula that the 6 coordinate valences of the cobalt atom (Co2+ )are satisfied by the 4 nitrogens of the reduced tetrapyrrole, a nitrogen atom of 5, 6-dimethylbenzimidazole and a cyanide ion. Two of the pyrrole rings, namely A and D, are directly linked to each other and the corrin has lower degree of unsaturation with only 6 double bonds. The other two pyrrole rings, namely B and C, are joined through a single methene carbon. Another distinct feature of the vitamin B12 molecule is the presence of a loop of the isopropanol, phosphate, ribose and 5,6-dimethyl-benzimidazole in that order, the end of the loop being attached to the central cobalt atom. Many compounds with vitamin B12 activity have been isolated from natural sources. Cyanocobalamin is the most common form and is sometimes also written as vitamin B12a. In other forms, cyanide ion is replaced by other ions, e.g., by hydroxyl ion in hydroxocobalamin (also designated as vitamin B12b), by nitrite ion in nitrocobalamin (also designated as vitamin B12c) etc. The latter two, B12b and B12c can be converted to vitamin B12a by treatment with cyanide.The structure of vitamin B12 coenzyme ( = 5′-deoxyadenosyl cobalamin) is similar to that of cobalamin except that here the CN group is replaced by adenosine and the linking with cobalt atom taking place at 5′ carbon atom of the ribose of adenosine. Vitamin B12 coenzyme is the only known example of a carbon-metal bond in a biomolecule.is surrounded by a macrocyclic structure of 4 reduced pyrrole rings (A, B, C and D) collectively called as corrin. It may be noted from the structural formula that the 6 coordinate valences of the cobalt atom (Co2+ )are satisfied by the 4 nitrogens of the reduced tetrapyrrole, a nitrogen atom of 5, 6-dimethylbenzimidazole and a cyanide ion. Two of the pyrrole rings, namely A and D, are directly linked to each other and the corrin has lower degree of unsaturation with only 6 double bonds. The other two pyrrole rings, namely B and C, are joined through a single methene carbon. Another distinct feature of the vitamin B12 molecule is the presence of a loop of the isopropanol, phosphate, ribose and 5,6-dimethyl-benzimidazole in that order, the end of the loop being attached to the central cobalt atom. Many compounds with vitamin B12 activity have been isolated from natural sources. Cyanocobalamin is the most common form and is sometimes also written as vitamin B12a. In other forms, cyanide ion is replaced by other ions, e.g., by hydroxyl ion in hydroxocobalamin (also designated as vitamin B12b), by nitrite ion in nitrocobalamin (also designated as vitamin B12c) etc.The latter two, B12b and B12c can be converted to vitamin B12a by treatment with cyanide.The structure of vitamin B12 coenzyme ( = 5′-deoxyadenosyl cobalamin) is similar to that ofcobalamin except that here the CN group is replaced by adenosine and the linking with cobalt atom taking place at 5′ carbon atom of the ribose of adenosine . Vitamin B12 coenzyme is the only known example of a carbon-metal bond in a biomolecule.
D. Properties. Vitamin B12 (molecular weight, ca 1,500) is a deep red crystalline substance.It is soluble in water, alcohol and acetone but not in chloroform. It is levorotatory. It is stable to heat in neutral solutions but is destroyed by heat in acidic or alkaline solutions.
E. Metabolism. Vitamin B12 is converted to coenzyme B12 by extracts from microorganisms
supplemented with ATP.
Coenzyme B12 is associated with many
biochemical reactions :
(a) 1,2 shift of a hydrogen atom : Coenzyme B12 catalyzes 1,2 shift of a hydrogen atom from one carbon atom of the substrate to the next with a concomitant 2,1 (reverse) shift of some other group, e.g., hydroxyl, alkyl etc.
(b) Carrier of a methyl group : Coenzyme B12 also serves as a carrier of a methyl group,obtained from
N5-methyltetrahydrofolate, to the appropriate acceptor molecule.In the reaction, a methyl group occupies the 5-deoxyadenosyl coordination position of coenzyme B12. Methylation of homocysteine to produce methionine is an example of such reaction.
(c) Isomerization of dicarboxylic acids : Coenzyme B12 is associated with isomerization of dicarboxylic acids, e.g., glutamic acid into β-methyl-aspartic acid.supplemented with ATP.
Coenzyme B12 is associated with many
biochemical reactions :(a) 1,2 shift of a hydrogen atom : Coenzyme B12 catalyzes 1,2 shift of a hydrogen atom from one carbon atom of the substrate to the next with a concomitant 2,1 (reverse) shift of some other group, e.g., hydroxyl, alkyl etc.
(b) Carrier of a methyl group : Coenzyme B12 also serves as a carrier of a methyl group,obtained from
N5-methyltetrahydrofolate, to the appropriate acceptor molecule.In the reaction, a methyl group occupies the 5-deoxyadenosyl coordination position of coenzyme B12. Methylation of homocysteine to produce methionine is an example of such reaction.(d) Dismutation of vicinal diols : Coenzyme 12 also catalyzes dismutation of vicinal diols to the corresponding aldehydes, e.g., propane-1,2-diol into propionaldehyde. Vitamin B12 is also needed for the biosynthesis of methyl groups from 1-carbon precursors and for the synthesis of thymidine and other deoxyribosides. It also functions in protein synthesis and in the activation of SH enzymes. Cyanocobalamin also affects myelin formation.
F. Deficiency: A nutritional deficiency of this vitamin is usually not observed on account of its ubiquitous ( = widespread) nature in foodstuffs. Thus, most cases of deficiency stem from failure to absorb the vitamin. However, deficiency may be observed in individuals who abstain from all animal products including milk and eggs, i.e., those who are strict vegetarians.The rare disease juvenile (or congenital) pernicious anemia springs up due to an inability to secrete gastric intrinsic factors. The symptoms of this disease become prominent at 9 months to 10 years of age. As the anemia becomes severe, irritability, anorexia and listlessness occur. The tongue is smooth, red and painful. Neurologic symptoms include ataxia, paresthesias, hyporeflexia, clonus, Babinski responses and coma. Consanguinity is common in parents of affected children and suggests Mendelian recessive inheritance. The juvenile disease differs from the typical disease in adults in that the stomach secretes acid normally and is histologically normal.
This typical deficiency disease, adult pernicious anemia ( = anemia caused by failure of erythrocyte formation), is characterized by R.B.Cs. becoming abnormally large and fewer in number (1–3 million per cubic millimeter instead of the normal 4–5 million). The patient weakens, loses its weight and the nervous system is also gradually affected because there occurs demyelinization of the large nerve fibres of the spinal cord. All these changes ultimately lead to death.G. Human requirements: The recommended daily allowance of vitamin B12 is 2 to 4 μg for children and 5 μg for men and women. Pregnant and lactating mothers require 8 μg and 6μg daily.
H. Treatment : The excessive secretion of methylmalonic acid in the urine is a reliable andsensitive index of vitamin B12 deficiency. The physiologic need for vitamin B12 is 1-5 μg/24 hr,and hematologic responses have been observed with these small doses. If there is evidence of neurologic involvement, 1 mg should be injected intramuscularly daily for a minimum of 2 weeks.Maintenance therapy is necessary throughout patient’s life; monthly intramuscular administration of 1 mg of vitamin B12 is sufficient.
H. Treatment : The excessive secretion of methylmalonic acid in the urine is a reliable andsensitive index of vitamin B12 deficiency. The physiologic need for vitamin B12 is 1-5 μg/24 hr,and hematologic responses have been observed with these small doses. If there is evidence of neurologic involvement, 1 mg should be injected intramuscularly daily for a minimum of 2 weeks.Maintenance therapy is necessary throughout patient’s life; monthly intramuscular administration of 1 mg of vitamin B12 is sufficient.
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