An Overview of Homocysteine Metabolism - Homocysteine in Protein Structure/Function and Human Disease - page 6

Chapter 2
An Overview of Homocysteine Metabolism

Mammals, in contrast to bacteria and plants, cannot make their own methionine
(Met). Thus, in humans and animals, Met is an essential amino acid that is provided
in the form of proteins ingested as food. In our digestive tract dietary proteins are
hydrolyzed to amino acids. Met released from dietary proteins is taken up by the
epithelium of the digestive tract and transported in the blood to cells of various
organs. In every cell of the body Met is metabolized by two major pathways
(Fig. 1.1 ): (1) as a building block to make new proteins in the ribosomal protein
biosynthetic apparatus and (2) as a precursor of S-adenosylmethionine (AdoMet), a
universal donor that provides methyl groups for biological methylation reactions
and propyl groups for polyamine biosynthesis (both derived from Met). In meta-
bolic pathways (1) and (2), Met is activated by reactions with ATP, albeit in a
pathway-specific manner: the carboxyl group of Met is activated in pathway (1),
while the thioether sulfur atom is activated in pathway (2).
It is the Met utilization pathway (2) that eventually leads to Hcy [20] (Fig. 1.1 ).
As a result of the transfer of its methyl group to an acceptor, AdoMet is converted to
S-adenosylhomocysteine (AdoHcy). The reversible enzymatic hydrolysis of
AdoHcy is the only known source of Hcy in the human or animal body. Levels of
Hcy are regulated by remethylation to Met, catalyzed by the enzyme MS, and a
two-step transsulfuration to cysteine, the first step of which is catalyzed by the
enzyme CBS, while the second step is catalyzed by cystathionine -lyase (CSE).

The remethylation catalyzed by MS requires vitamin B 12 and 5,10-methyltetrahy-
drofolate (CH 3 -THF), generated by MTHFR [31] (Fig. 1.1 ). An alternative
remethylation pathway is catalyzed by betaine-Hcy methyltransferase (BHMT)
[80]. The transsulfuration requires vitamin B 6 . While remethylation by MS occurs
in every organ of the body, remethylation by BHMT and transsulfuration by CBS
are limited to the liver and kidneys. Hcy can also react oxidatively with other thiols,
mainly sulfhydryl groups of extracellular proteins, to formmixed disulfides (S-Hcy-
protein) [78, 79, 81].
A fraction of Hcy is also metabolized by methionyl-tRNA synthetase (MetRS in
Fig. 1.1 ) to the thioester Hcy-thiolactone [68, 69, 82, 83]. The flow through the
Hcy-thiolactone pathway is increased by a high-Met diet (the ultimate precursor of

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