B12 METABOLISM IN HUMANS By NICOLE AURORA LEAL A ...
B12 METABOLISM IN HUMANS By NICOLE AURORA LEAL A ...
B12 METABOLISM IN HUMANS By NICOLE AURORA LEAL A ...
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methylmalonic acid. Methylmalonic acid is excreted into the urine, resulting in<br />
methylmalonic aciduria, an inherited disorder that is often fatal in newborns.<br />
Methionine synthase<br />
MS catalyzes the conversion of CH3THF and homocysteine to THF and<br />
methionine. This enzyme is found in both bacteria and humans. In E. coli, two MS<br />
enzymes occur and they differ in their requirement for CH3Cbl (Drummond and<br />
Matthews 1993). In humans, only CH3Cbl-dependent MS is present. The E. coli and<br />
human genes encoding CH3Cbl-dependent MS have been cloned and encode large<br />
9<br />
monomeric proteins of 136 and 141 kDa, respectively (Banerjee et al. 1989, Leclerc et al.<br />
1996). The human gene was mapped to chromosome 1 at position q43 (Leclerc et al.<br />
1996). The bacterial and the human enzymes share 55% identity in amino acid sequence,<br />
and have established similarities in the mechanism of catalysis (Hall et al. 2000).<br />
However, only the E. coli CH3Cbl-dependent MS has been studied extensively.<br />
Methionine synthase from E. coli is a modular enzyme consisting of four domains,<br />
all of which are crucial for enzyme catalysis (Goulding et al. 1997). The N-terminal<br />
domain (residues 2-353) has been cloned, expressed, and shown to be involved in<br />
homocysteine binding, and methyl group transfer from CH3Cbl to homocysteine<br />
(Goulding et al. 1997). It contains three cysteine residues used to coordinate a zinc ion<br />
essential for homocysteine binding, which are conserved in other MS enzymes including<br />
Homo sapiens, Caenorhabditis elegans, and Synechocystis species (Goulding and<br />
Matthews 1997). The second domain (residues 354-649) was shown to catalyze methyl<br />
transfer from CH3THF to cob(I)alamin (Goulding et al. 1997). The third domain<br />
(residues 650-896) was lacking enzymatic activity; however, it was shown to be essential<br />
for CH3Cbl binding (Banerjee et al. 1989). This fragment was crystallized and shown to