Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.2.1.22 (cystathionine beta-synthase)
 965 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Homocysteine is a branch-point metabolite, the biological fate of which is linked to vitamin B12, reduced folates and vitamin B6. Various inborn defects in homocysteine metabolism, among which cystathionine beta-synthase deficiency is most common, lead to the clinical condition homocystinuria. A central feature of this clinical state is premature arteriosclerosis. These patients benefit from agents serving as cofactors in homocysteine metabolism which both reduce the homocysteine levels in plasma and the incidence of vascular episodes. Experimental data point to homocysteine as an arteriosclerotic agent. Homocysteine in human plasma exists mainly as mixed disulfides with albumin (70 per cent) and cysteine. New methods determine total plasma homocysteine which includes all these species. Normal values for plasma homocysteine are lower in premenopausal women than in men and postmenopausal women. Impaired homocysteine metabolism seems to exist in 15-30 per cent of patients with premature cardiovascular disease. Moderate homocysteinemia is as a risk factor for cardiovascular disease, independent of conventional risk factors. Apart from homocystinuria, vitamin B12 deficiency causes the most extreme elevations of plasma homocysteine, and it has been established that plasma homocysteine is a more responsive parameter to impaired vitamin B12 function than serum cobalamin. Massive increase in plasma homocysteine level is also observed in folate deficiency, whereas renal failure, some malignant states and psoriasis cause a moderate homocysteinemia. High doses of folic acid reduce plasma homocysteine, and this innocuous mean should be considered as an intervention in patients with increased plasma level. Drugs like methotrexate, some anticonvulsants and 6-azauridine triacetate induce moderate elevation of plasma homocysteine, whereas a reduction is observed after penicillamine administration.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Plasma homocysteine, a risk factor for premature vascular disease. Plasma levels in healthy persons; during pathologic conditions and drug therapy]. 281 54

High homocysteine (Hcy) levels are a well-known independent risk factor for endothelial damage in atherosclerosis. We examined whether a rat intestinal model of ischemia-reperfusion was associated with high Hcy and with the modification of plasma albumin into cysteinylated species (CysAlb). The three treatment groups were as follows: midline abdominal incision (group A, n=10), followed by ligation of the superior mesenteric artery for a period of 2h (group B, n=3), and followed by reperfusion for 1h (group C, n=10). Hcy levels were 2.5-fold higher in group C than group A (p<0.05). 100% and 73.44+/-0.04% of Alb were modified into Cys species in groups C and B, respectively, compared to 51.2% in group A. A cystathionine beta-synthase (CBS) deficient mouse model, known to have high plasma Hcy levels, was also used to determine the extent of CysAlb. Hcy levels, %CysAlb, and %HcyAlb were 180.1+/-45.7 microM, 0%, and 23.4+/-4.4% in CBS deficient mice, while in control mice, those values were 5.7+/-1.8 microM, 24.2+/-4.1%, and 0%, respectively (p<0.05). High CysAlb and Hcy levels were observed in a rat model of bowel ischemia/reperfusion while high HcyAlb and Hcy levels with no CysAlb were observed in the CBS deficient mice. CysAlb may serve as a biomarker for the severity of gut ischemia, and high Hcy may explain endothelial damage associated with this model. Additionally, active CBS is essential for the formation of CysAlb.
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PMID:Plasma albumin cysteinylation is regulated by cystathionine beta-synthase. 1555 90

Copper was added to truncated, recombinant cystathionine beta-synthase (CBS), and the enzyme activity was assessed by measuring the production of cystathionine. 10 microM copper significantly decreased CBS activity by 50% while 25 microM copper decreased CBS activity by 70%. This inhibition was negated when an analog of the N-terminus of human albumin, Asp-Ala-His-Lys (DAHK), a strong transition metal binding peptide, was added. The use of copper chelators could significantly reduce in vivo homocysteine levels.
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PMID:Inhibitory effect of copper on cystathionine beta-synthase activity: protective effect of an analog of the human albumin N-terminus. 1577 77

Accumulating evidence suggests that homocysteine (Hcy) metabolite, the thioester Hcy-thiolactone, plays an important role in atherothrombosis. Hcy-thiolactone is a product of an error-editing reaction in protein biosynthesis which forms when Hcy is mistakenly selected by methionyl-tRNA synthetase. The thioester chemistry of Hcy-thiolactone underlies its ability to from isopeptide bonds with protein lysine residues, which impairs or alters protein's function. Protein targets for the modification by Hcy-thiolactone include fibrinogen, low-density lipoprotein, high-density lipoprotein, albumin, hemoglobin, and ferritin. Pathophysiological consequences of protein N-homocysteinylation include protein and cell damage, activation of an adaptive immune response and synthesis of auto-antibodies against N-Hcy-proteins, and enhanced thrombosis caused by N-Hcy-fibrinogen. Recent development of highly sensitive chemical and immunohistochemical assays has allowed verification of the hypothesis that the Hcy-thiolactone pathway contributes to pathophysiology of the vascular system, in particular of the prediction that conditions predisposing to atherosclerosis, such as genetic or dietary hyperhomocysteinemia, lead to elevation of Hcy-thiolactone and N-Hcy-protein. This prediction has been confirmed in vivo both in humans and in mice. For example, plasma Hcy-thiolactone was found to be elevated 59-72-fold in human patients with hyperhomocysteinemia secondary to mutations in methylenetetrahydrofolate reductase (MTHFR) or cystathionine beta-synthase (CBS) genes. Plasma N-Hcy-protein levels are elevated 24-30-fold in MTHFR- or CBS-deficiency, both in human patients and in mice. Plasma and urinary Hcy-thiolactone and plasma N-Hcy-protein levels are also elevated up to 30-fold in mice fed a hyperhomocysteinemic (1.5% methionine) diet. Furthermore, plasma levels of prothromobogenic N-Hcy-fibrinogen were elevated in human CBS deficiency, which explains increased atherothrombosis observed in CBS-deficient patients. We also observed increased immunohistochemical staining for N-Hcy-protein in aortic lesions from ApoE-deficient mice with hyperhomocysteinemia induced by a high methionine diet, relative to the mice fed a normal chow diet. We conclude that genetic or dietary hyperhomocysteinemia significantly elevates proatherothrombotic metabolites Hcy-thiolactone and N-Hcy-proteins in humans and mice.
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PMID:The pathophysiological hypothesis of homocysteine thiolactone-mediated vascular disease. 1926 78

A posttranslational protein modification by homocysteine-thiolactone (N-homocysteinylation) is linked to human vascular and neurodegenerative diseases. Although chemical and immunological methods are available to detect and quantify the extent of protein N-homocysteinylation, the determination of site-specific N-homocysteinylation in vivo remains challenging. Here we describe a liquid chromatography/mass spectrometry method that monitors the extent of N-homocysteinylation at albumin lysine-525 in vivo directly in human serum. Using this method, we found that the extent of lysine-525 N-homocysteinylation was significantly increased in patients with cystathionine beta-synthase deficiency.
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PMID:Direct monitoring of albumin lysine-525 N-homocysteinylation in human serum by liquid chromatography/mass spectrometry. 2065 4