Homocysteine: A Risk Factor for Atherothrombotic Cardiovascular Disease
P. K. Shah in Risk Factors in Coronary Artery Disease, 2006
Homocysteine is a sulfur amino acid formed during the metabolism of methionine, an essential amino acid that is found in dietary protein. Homocysteine is metabolized by remethylation or transsulfuration (Fig. 1) (1). Remethylation is a salvage pathway; homocysteine acquires a methyl group from 5-methyl-tetrahydrofolate to form methionine in a reaction catalyzed by the vitamin B12-dependent enzyme, methionine synthase. 5-methyl-tetrahydrofolate is derived from folate in a cycle catalyzed by methylene tetrahydrofolate reductase (MTHFR). An alternative pathway for remethylation occurs in the liver, where betaine acts as the methyl donor. Transsulfuration occurs during times of methionine excess or cysteine depletion. Homocysteine combines with serine to form cystathionine via a rate-limiting reaction catalyzed by the B6-dependent enzyme, cystathionine-beta-synthase. Cystathionine-gamma-lyase, another B6-dependent enzyme, then catalyzes the hydrolysis of cystathionine to cysteine, which is then further metabolized to glutathione or sulfate (2).
Biochemical Effects in Animals
Stephen P. Coburn in The Chemistry and Metabolism of 4′-Deoxypyridoxine, 2018
Efremova et al.132 studied in inhibition of cystathionine beta syntheses from the livers of rats and chickens by various B6 analogs after simultaneous incubation of the apoenzyme with the analog (10−4M) and pyridoxal phosphate (2 × 10−3M). The article refers to the chicken enzyme as serine sulfhydrase (E.C. 4.2.1.22) and the rat enzyme as cystathionine-beta-synthase (E.C. 4.2.1.21). However, the 1972 revision of the IUB recommendations combined these entries under one heading, cystathionine-beta-synthase (E.C. 4.2.1.22). Pyridoxine phosphate was neither an activator nor an inhibitor of the enzymes. 4′-Deoxypyridoxine-5′-phosphate was not an activator but apparently was not tested as an inhibitor. 3-Deoxypyridoxal-phosphate produced 33% inhibition in the chicken enzyme and 20% inhibition in the rat enzymes. As was the case with glutamate decarboxylase there was no evidence that the 3-deoxypyridoxal formed an aldimine bond with the enzyme. 5′-Deoxypyridoxal produced 15 and 30% inhibition of the rat and chicken enzymes, respectively.
Homocystinuria
Charles Theisler in Adjuvant Medical Care, 2023
Pyridoxine is the drug of choice. Eleven patients were treated with pyridoxine (300– 450 mg/day) with six of those patients achieving normal or near-normal homocysteine levels.2 Folic acid should be given in all cases where pyridoxine is used because it causes further biochemical improvement in pyridoxine responsive patients and subjective clinical improvement in all.3 Pyridoxine at 10 mg/kg/day up to a maximum of 500 mg/day for six weeks is recommended for infants with homocystinuria.1 About 50% of patients have a form of cystathionine beta-synthase deficiency that improves biochemically and clini cally through pharmacologic doses of pyridoxine (50–500 mg/ day) and folate (5–10 mg/day).4,5,6
Cystathionine β-synthase Deficiency Impairs Vision in the Fruit Fly, Drosophila melanogaster
Published in Current Eye Research, 2021
Marycruz Flores-Flores, Leonardo Moreno-García, Felipe Castro-Martínez, Marcos Nahmad
Classic homocystinuria is a metabolic disease mainly caused by inherited deficiency of Cystathionine-β-synthase (CBS), a vitamin B6-dependent enzyme that catalyzes the flux of sulfur from methionine to cysteine in the transsulfuration pathway.1 In humans, genetic variants causing low CBS expression lead to the accumulation of toxic levels of homocysteine and methionine in urine and plasma, affecting skeletal, visual, the central nervous system,2,3 and also poses an independent risk factor for thrombosis and vascular disease.4,5 One of the most common clinical manifestations of homocystinuria is severe myopia followed by ectopia lentis that affects about 90% of patients with a CBS deficiency.6,7 Despite the high prevalence of eye-related abnormalities caused by this disease, the molecular mechanisms that relate CBS deficiency to vision problems are poorly understood. Murine models of genetic deficiency of cbs have been used as a model of homocystinuria,8,9 including visual manifestations. For instance, studies using cbs-mutant mice have reported alterations of retinal vasculature,10 retinal ganglion cell death,11,12 and visual function.13 However, the widespread use of this experimental model is challenging due to a large degree of neonatal lethality.9
Givosiran for the treatment of acute hepatic porphyria
Published in Expert Review of Clinical Pharmacology, 2022
Some authors have reported, together with homocysteine, a concurrent increase in methionine levels [64,67], which may hint at a specific dysfunction of cystathionine beta-synthase (CBS), a vitamin B6–dependent enzyme that relies on heme for regulatory functions (the trans-sulfuration pathway of homocysteine catabolism starts with CBS). In principle, the inhibitory action of givosiran on the first and rate-limiting enzyme of heme biosynthesis could have an impact on the non-erythropoietic routes of heme utilization. In this case, even though vitamin B6 supplementation, used alone, may be effective in increasing CBS activity, a more complete supplementation therapy may provide a beneficial enhancement of both routes of homocysteine catabolism (trans-sulfuration and remethylation). Moreover, as the metabolism of amino acids and heme biosynthesis are complexly intertwined, it cannot be excluded that hyperhomocysteinemia is the result of more complex interactions that may benefit from a more complete integration of vitamins and cofactors. While further studies are needed before reaching consensus recommendations, it should be considered that all patients eligible for givosiran be screened for basal homocysteine levels and hyperhomocysteinemia-related vitamin status before starting treatment and periodically while on treatment with givosiran [65,68]. Adequate supplementation therapy can be considered in cases of hyperhomocysteinemia.
Low CBS expression can identify patients who benefit from adjuvant chemotherapy in gastric cancer
Published in Expert Review of Anticancer Therapy, 2021
Jinsheng Zhao, Yusheng Zhao, Shasha Ding, Tao Liu, Fanzheng Meng
Cystathionine β-synthase (CBS), a fundamental enzyme in L-cystathionine synthesis, catalyzes the initial step of the transsulfuration pathway: the condensation of serine and homocysteine to generate cystathionine [34]. A large body of evidence has revealed the involvement of CBS in tumor progression, including ovarian [6], colorectal [7,8], breast [9], lung [10,11], renal [12,13], thyroid [14], bladder [15], and gallbladder [16]. However, the role of CBS in Hepatocellular Carcinoma and GC is still conflicting and inconclusive. The CBS mRNA level was markedly decreased in hepatocellular carcinoma tissues compared to the surrounding noncancerous tissues. Lower CBS expression was significantly associated with poor clinicopathological features and overall survival [17]. Intriguingly, Jia et al. [35] found silencing or inhibiting CBS in the SMMC-7721 HCC cell line reduced H2S production, decreased cell viability, and enhanced ROS production in vitro. In GC, Zhang et al. [18] found CBS was up-regulated in tumor tissues while Zhao et al. [19] found CBS was down-regulated by promoter hypermethylation in tumor tissues. In our study, we utilized the large sample from TCGA and NCBI GEO database and found CBS mRNA expression was significantly lower in GC tissues compared to adjacent tissues. Data from Human Protein Atlas also suggested CBS protein expression was not detected by immunohistochemistry in all eleven GC tissue samples. In addition, we also identified hypermethylation of CBS promoter in GC, which was negatively associated with low expression of CBS, consistent with the results in the report from Zhao et al. [19].
Related Knowledge Centers
- Allosteric Regulation
- Cofactor
- Cystathionine
- Enzyme
- Homocysteine
- Pyridoxal Phosphate
- Gene
- Transsulfuration Pathway
- Serine
- Properties of Water