B12 METABOLISM IN HUMANS By NICOLE AURORA LEAL A ...

CHAPTER 2
IDENTIFICATION OF THE HUMAN AND BOVINE ATP:COB(I)ALAMIN
ADENOSYLTRANSFERASE CDNAS BASED ON COMPLEMENTATION OF A
BACTERIAL MUTANT
Introduction
Enzymes dependent on the vitamin B12 coenzymes, AdoCbl and CH3Cbl have a
broad but uneven distribution among the three domains of life (Dolphin 1982, Schneider
and Stroinski 1987, Banerjee 1999). In higher animals, there are two known
cobalamin-dependent enzymes. CH3Cbl dependent MS is needed for the methylation of
homocysteine to methionine (Cauthen et al. 1966, Drummond and Matthews 1993), and
AdoCbl-dependent MCM plays an essential role in the conversion of propionyl-CoA to
the TCA cycle intermediate, succinyl-CoA (Banerjee and Chowdhury 1999, Matthews
1999). This latter process occurs in three steps: propionyl-CoA is carboxylated to
(2S)-methylmalonyl-CoA, isomerized to (2R)-methylmalonyl-CoA, and finally
rearranged to succinyl-CoA in a reaction catalyzed by AdoCbl-dependent MCM
(Figure 1-3). In higher animals, propionyl-CoA is produced from the breakdown of the
amino acids valine, isoleucine, methionine, and threonine, as well as thymine, cholesterol
and odd-chain fatty acids; hence, MCM is essential for the complete catabolism of each
of these compounds (Banerjee and Chowdhury 1999).
In humans, inherited defects that impair the activity of AdoCbl-dependent MCM
lead to methylmalonic aciduria, a rare but severe disease that is often fatal in the first year
of life (Rosenblatt and Fenton 1999, Fenton et al. 2000, Olteanu and Banerjee 2001).
Such inherited deficiencies can result from mutations in the MCM structural gene (mut)
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