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

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homocysteine recycling and methionine synthesis. Deficiencies in MCM or MS can lead
to methylmalonic aciduria or homocystinuria (rare but often lethal childhood disorders).
Methylmalonyl-CoA mutase
MCM is the only AdoCbl-dependent enzyme that is present in both bacterial and
mammalian systems. In humans, it resides in the mitochondrial matrix, and is used for
the metabolism of propionyl-CoA to succinyl-CoA. In this metabolic pathway,
propionyl-CoA is carboxylated to (2S)-methylmalonyl-CoA, isomerized to
(2R)-methylmalonyl-CoA, and lastly rearranged to succinyl-CoA by MCM (Figure 1-3).
In contrast, in some bacteria including Propionibacterium shermanii, MCM is used in the
opposite metabolic flow to produce propionate from succinate (Allen et al. 1964).
The gene encoding MCM has been sequenced and cloned from many organisms
including human, P. shermanii, mouse, Streptomyces cinnamonensis, Porphyromonas
gingivalis, and Sinorhizobium meliloti (Banerjee and Chowdhury 1999). In humans, the
location of the MCM gene was mapped to chromosome 6p12-21.2, and the cDNA was
shown to have a mitochondrial targeting sequence (MTS) (Ledley et al. 1988).
In native conformation, the human and bacterial MCMs are 150 kiloDaltons (kDa),
and are dimeric proteins. The crystal structure of P. shermanii MCM has been
determined, and is an αβ heterodimer that binds one mole of AdoCbl (Marsh et al. 1989).
The human MCM is a homodimer of two α subunits that binds two moles of AdoCbl and
has 60% sequence identity to the α chain of the bacterial MCM (Mancia et al. 1996).
UV, visible, and electron paramagnetic resonance spectroscopic studies have
shown that AdoCbl binding by MCM occurs via “Base-off” (class I) interaction
(Padmakumar and Banerjee 1995). “Base-off” binding occurs by the displacement of the