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BIOSYNTHESIS OF
VITAMIN B12

CONTENTS
• INTRODUCTION
• BIOSYNTHESIS OF VITAMIN B12
• DEFICIENCY
• REFERENCES

Vitamin B12
• Vitamin B12, also called cobalamin, is a watersoluble vitamin that is involved in the metabolism
of every cell of the human body
...

• It is particularly important in the normal
functioning of the nervous system via its role in the
synthesis of myelin, and in the maturation of
developing red blood cells in the bone marrow
...

• It contains the biochemically rare element cobalt
positioned in the center of a corrin ring
...
This core of the molecule is
known as a corrin ring
...

• The only organisms to produce vitamin B12 are certain
bacteria, and archaea
...


Biosynthesis of vitamin B12
Two distinct biosynthetic pathways exist, which are
termed the aerobic and anaerobic routes
...

Aerobic pathway that requires oxygen and in which
cobalt is inserted late in the pathway; found in
Pseudomonas denitrificans and Rhodobacter
capsulatus
...


Biosynthesis of
vitamin B12
Transformation of UroporphyrinogenThe overall transformation of uroporphyrinogen III into
vitamin B12 requires a number of peripheral C-methylations,
ring contraction with the loss of the C-20 meso position,
cobalt chelation, amidation of the majority of the carboxylic
acid side chains, decarboxylation of the acetic acid side
chain on ring C, aminopropanol attachment, adenosylation
and attachment of the lower base in the from of α-ribazole
...


• Either pathway can be divided into two parts:
• Corrin ring synthesis (differs in aerobic and anaerobic
pathways)
• Adenosylation of corrin ring, attachment of
aminopropanol arm, and assembly of the nucleotide
loop (common to both pathways)
...


Uroporphyrinogen III
methyltransferase
• Uroporphyrinogen III methyltransferases catalyse
the transformation of uroporphyrinogen III into
precorrin-2
...

• A monomethylated compound (precorrin-1,
methylated at C-2) is initially synthesised and
released from the protein and subsequently used
as the substrate for the second (C-7)methylation
...

• The product of the previous (CobI) reaction was termed
precorrin-3A whilst the new intermediate was termed
precorrin-3B
...

• CobG therefore produces an intermediate that is set up or
“spring loaded” for ring contraction whilst the actual ring
contraction process is catalysed by the C-17
methyltransferase CobJ
...


Precorrin-5 and 6
• CobM was responsible for the synthesis of precorrin-5, which would
have been predicted to occur via methylation at position C-12
...

• This reaction is catalysed by CobF and is concomitant with the loss of
the acetyl group as acetic acid
...

• It was pointed out that methylation at C-11 produces a conjugated
system to hasten the elimination of the acetyl group by a reverse
Claisen condensation
...

• The final product of this reaction is precorrin 6A
...


Amidations, cobalt chelation and
adenosylation
• With the synthesis of the corrin ring now complete, the next
steps is amidation of the side chains and the insertion of the
central cobalt ion
...
32
The enzyme requiresMg2/ATP and glutamine for activity and
generates hydrogenobyrinic
• acid a,c-diamide by amidating first the c and then the a side
chain
...

• The first componentis made from CobN,, whilst the second is
made from CobS and T
...
6), indicating that there hasbeen no redox
change associated with the chelation process
...
To do this the
cobalt ionis reduced by a reductase
...
33 The enzyme
has
• a high affinity for cob(I)yrinic acid a,c-diamide producing
• adenosylcob(III)yrinic acid a,c-diamide but is strongly
• inhibited by the cobalt-free substrate equivalent,
hydrogenobyrinic acid a,c-diamide
...


•ANAEROBIC
BIOSYNTHESIS OF
ADENOSYLCOBYRIC ACID
•EARLY COBALT CHELATION
• The enzyme that performs this task
• in S
...


Cobalt-dependent ring contraction
• The true biosynthetic intermediate is likely to be the dihydroversion of this compound, cobalt-precorrin-4
...
It contains a δlactone formed from the C-2 acetic acid side methylated C-20
position, which is now linked only to C-1
...


Methyltransferase structure
• The next step in the anaerobic pathway beyond
cobalt-precorrin-4 would be expected to be
methylation at C-11, which should be undertaken
by the next methyltransferase, CbiF
...
In the anaerobic
pathway homologues are present for all the specific
methylases except that no equivalent is found for
CobF
...
11)
...
denitrificans, this
• process is accomplished by a two component
system, designated α and β
...


The guanylyltransferase activity of
CobU
• The conformational change that occurs upon selfguanylylation of CobU is essential for both kinase
and guanylyltransferase activities of the enzyme
...

• It has been shown that the guanylyl group of the
CobU-GMP intermediate is incorporated into
AdoCbi-GDP
...

• Vitamin B12 deficiency is most commonly caused
by low intakes, but can also result from
malabsorption, certain intestinal disorders, low
presence of binding proteins, and use of certain
medications
...
lt is characterized by low
hemoglobin levels, decreased number of erythrocytes
and neurological manifestations
...

• 1
...
In the absence of lF, vitamin 812
cannot be absorbed
...
Hereditary malabsorption of vitamin B12
...
The
symptoms include paresthesia (numbness and tingling)
of fingers and toes
...

• The neurological symptoms of pernicious anemia are
believed to be due to the accumulation of methylmalonyl
CoA that interferes in myelin sheath formation

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