An Overview of Homocysteine Metabolism - Homocysteine in Protein Structure/Function and Human Disease - page 9

possesses a cysteine residue with free -SH group that is capable of forming a
disulfide bond with a low molecular thiol.
In addition to S-linked Hcy, albumin, γ -globulin [107-109], transthyretin [104,

105, 110], α 1 -acid glycoprotein, and HDL [106] are known to carry S-linked

cysteine, CysGly, and glutathione (GSH) in vivo. In normal human plasma the
concentration of protein S-linked Hcy (10 μ M) is lower than the concentration of

protein S-linked Cys (165 μ M) and CysGly (17 μ M), but higher than the concentra-

tion of protein S-linked GSH (1.5 M) [111]. In erythrocytes the bulk of blood

S-GSH-protein occurs as S-GSH-hemoglobin, which, with a concentration of
130 μM, comprises 14 % of erythrocyte GSH content [112].
The presence of S-Hcy-protein has also been reported in the liver, kidney, and
brain tissues from a patient with MTHFR deficiency at autopsy, but not in tissues
from three subjects who died of unrelated causes [91]. Much higher levels of
S-Hcy-protein accumulate in the brain (403.1 pmol/mg protein) than in the liver
(76.1 pmol/mg protein) and kidney (55.2 pmol/mg protein) of the MTHFR-defi-
cient patient. The level of liver S-Hcy-protein in the MTHFR-deficient patient
(76.1 pmol/mg protein) [91] is lower than the level of liver tHcy in Mthfr /
mice (184

μ

7) [113].
In rodents, tHcy concentrations in tissues and plasma are similar, in the micro-
molar range [114]. Significant pools of Hcy bound to intracellular proteins by
disulfide linkages (S-Hcy-protein) exist in rodent tissues and plasma [114]. For
example, S-Hcy-protein comprises ~42 % of tHcy in rat liver, kidney, heart, and
lung. In rat cerebrum and cerebellum S-Hcy-protein constitutes 30.4 % and 5.3 %,
respectively, of tHcy.

71 μ M, n ¼

2.1.3 Homocysteine-Thiolactone

In normal humans and mice, plasma Hcy-thiolactone concentrations are in the
subnanomolar to low nanomolar range, whereas urinary Hcy-thiolactone
concentrations are ~100-fold higher (Table 2.1 ) [93-95]; > 95 % of the filtered
plasma Hcy-thiolactone is cleared by the kidney [93, 95]. Plasma Hcy-thiolactone
is elevated 59- to 237- and 72-fold in human MTHFR and CBS deficiency,
respectively, and 14-fold in mice fed with a high methionine diet.

2.1.4 N -Homocysteinyl-Protein

N-linked Hcy is carried on all blood proteins that have been examined, including
hemoglobin, albumin, -globulin, fibrinogen, transferrin, antitrypsin, LDL, and HDL

[79]. In normal human and mouse blood, N-Hcy-protein concentrations are in the
submicromolar to low micromolar range (Table 2.1 ) and increase 10-20-fold in
genetic or dietary hyperhomocysteinemia [79, 113, 115]. The levels of N-Hcy-protein

γ