Introduction - Homocysteine in Protein Structure/Function and Human Disease - page 1

Chapter 1
Introduction
That homocystine itself might be present in proteins is a
possibility that should be borne in mind and will be worth
investigating
—Vincent Du Vigneaud, 1955 Nobel Prize in Chemistry
laureate
In living organisms, homocysteine (Hcy) is a universal intermediate in the meta-
bolic pathways of two other sulfur-containing amino acids: cysteine and methio-
nine. Relative to cysteine, Hcy has in its side chain an extra methylene (-CH 2 -)
group that makes it a higher homolog of cysteine. Compared with methionine, Hcy
is missing a methyl (CH 3 -) group and thus is a lower homolog of methionine.
Methionine and cysteine are two canonical coded amino acids that are incorporated
by the ribosomal biosynthetic apparatus into polypeptide chains of protein at
positions specified by AUG and UGU/UGC codons, respectively. In contrast,
Hcy does not normally participate in protein biosynthesis (there is no codon triplet
for Hcy) and is considered to be a nonprotein amino acid.
The disulfide cystine, the first sulfur-containing amino acid to be discovered,
was originally isolated from a urinary calculus by Wallastone in 1810 and, by the
end of nineteenth century, established to be a major component of proteins [1].
Since the mid-1800s accumulating experimental evidence from the Liebig's labo-
ratory and from other investigators indicated that cysteine does not account for all
the sulfur present in proteins [1]. The nature of this non-cystine protein sulfur has
been clarified in the 1923 studies of Mueller which led to the isolation of a new
sulfur-containing amino acid, methionine, from protein hydrolysates [2].
Hcy, the last of the three major sulfur-containing amino acids, was first obtained
in 1932 in the oxidized disulfide form—homocystine—by the demethylation of
methionine with sulfuric acid [3]. Three years later, in 1935, Hcy was prepared by
reduction of homocystine with metallic sodium in liquid ammonia [4]. Subsequent
studies clarified the physiological role of Hcy as an intermediate in the metabolism
of methionine and cysteine via the classical remethylation and transsulfuration
pathways, respectively [5].
Elucidation of the genetic code and of the ribosomal protein biosynthesis
mechanism established that Hcy is not a coded amino acid. However, because of