Homocysteine biosynthesis in green plants: studies of the homocysteine-forming sulfhydrylase.
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Bacteria↗
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Association between plasma homocysteine levels and P-wave dispersion in pediatric patients with hyperhomocysteinemia.
UNLABELLED: Hyperhomocysteinemia has been recognized as a cardiovascular risk factor associated with endothelial dysfunction, oxidative stress, and vascular inflammation. Experimental and clinical studies suggest that elevated homocysteine levels may also influence myocardial electrophysiology and contribute to arrhythmogenesis. However, data regarding the relationship between homocysteine levels and electrocardiographic markers of atrial conduction in pediatric populations remain limited. This study aimed to evaluate the association between plasma homocysteine levels and electrocardiographic parameters, particularly P-wave dispersion, in children. This multicenter retrospective case-control study included pediatric patients evaluated in four tertiary pediatric metabolism centers between January 2023 and December 2025. A total of 47 patients with hyperhomocysteinemia (plasma total homocysteine ≥ 15 µmol/L) and 43 age- and sex-matched controls with normal homocysteine levels were included. Controls were selected from the screened population among children with available homocysteine measurements, electrocardiographic and echocardiographic evaluations, and no confirmed inherited metabolic disease or cardiac disorder. Clinical, biochemical, and electrocardiographic parameters, including maximum P-wave duration and P-wave dispersion, were retrospectively analyzed. A total of 90 participants were included, comprising 47 children with hyperhomocysteinemia and 43 healthy controls. P-wave dispersion and maximum P-wave duration were significantly higher in the hyperhomocysteinemia group compared with controls (48.96 [19.48-100.0] vs. 38.57 [10.57-71.19] ms, p < 0.001). Plasma homocysteine levels showed a moderate positive correlation with P-wave dispersion (ρ = 0.441, p < 0.001). These differences were more pronounced in children with higher homocysteine levels and in younger age groups (< 2 years and 2-14 years). In contrast, PR interval (p = 0.790) and QTc interval (p = 0.183) did not differ significantly between groups. Vitamin B12 levels were significantly lower in the hyperhomocysteinemia group (p = 0.013), while folate levels were comparable (p = 0.974). Although sodium, potassium, and magnesium levels differed significantly between groups, all values remained within normal physiological ranges. CONCLUSIONS: Children with hyperhomocysteinemia showed increased P-wave dispersion compared with controls. These findings suggest an association between elevated homocysteine levels and altered atrial conduction parameters in children. Further prospective studies are needed to determine the clinical significance of these findings. WHAT IS KNOWN: • Hyperhomocysteinemia is associated with cardiovascular risk and endothelial dysfunction. • Elevated homocysteine levels have been linked to cardiac electrophysiological alterations in adult populations. WHAT IS NEW: • Elevated homocysteine levels are associated with increased P-wave dispersion in children, with more pronounced effects observed in younger age groups. • These findings support an association between hyperhomocysteinemia and altered atrial conduction parameters in children.
Adolescent↗
Coordinated use of three homocysteine methyltransferases supports l-methionine biosynthesis and environmental adaptation among plant-associated bacteria.
Plant pathogens colonize multiple plant-associated habitats throughout their life cycle, encountering distinct nutrient conditions and microbial communities. l-methionine is required for bacterial growth and environmental adaptation. However, how plant pathogens coordinate l-methionine biosynthetic pathways to adapt to different plant-associated environments remains poorly understood. Here, using the plant pathogen Xanthomonas campestris pv. campestris strain XC1 as a model, we show that three homocysteine methyltransferase pathways allow XC1 to catalyze the final step of l-methionine biosynthesis using different methyl donors and cofactors under different environmental conditions. Bioinformatic and transcriptional analyses identified three homocysteine methyltransferase-associated operons in XC1, mesMXD, mmuPM, and metHRHaHb, corresponding to the MesD-, MmuM-, and MetHaHb-dependent pathways, respectively. MesD uses an endogenously synthesized methyl donor and functions as the dominant homocysteine methyltransferase under l-methionine-limiting conditions, supporting bacterial growth, intracellular l-methionine accumulation, and full virulence. Furthermore, MmuM enables XC1 to use plant-derived S-methylmethionine for l-methionine biosynthesis, whereas MetHaHb enables XC1 to use vitamin B12 supplied by a neighboring bacterium for l-methionine biosynthesis in co-culture. Expression analyses showed that mesMXD was the only homocysteine methyltransferase-associated operon that responded to l-methionine availability, and its expression also decreased when S-methylmethionine- or vitamin B12-dependent pathways supported l-methionine biosynthesis. Comparative genomic analysis further showed that the three-homocysteine methyltransferase configuration is conserved in Xanthomonas and is also present in other plant-associated bacteria. Together, these findings show that a plant pathogen can coordinate endogenous, plant-derived, and microbially supported homocysteine methyltransferase pathways to maintain l-methionine biosynthesis, providing a metabolic strategy for adaptation to plant-associated environments.
Methionine↗
Effect of DL-homocysteine on some hepatic folate enzymes and folate concentration in cobalamin-deficient rats.
Male weanling wistar rats were fed either a vitamin B12-deficient diet or a vitamin B12-deficient diet supplemented with DL-homocysteine for 12 weeks. The control group was given a vitamin B12-supplemented diet for 12 weeks. Hepatic folate, hepatic, 5,10-methylene THF reductase (EC 1.1.1.68) and hepatic 5-methyl THF; homocysteine methyl transferase (EC 2.1.1.13) activities were assayed in all the rats after killing. The hepatic folate activity was very low among the homocysteine-supplemented rats. 5,10-methylene THF reductase and 5-methyl THF; homocysteine methyl transferase activities were increased in the homocysteine-fed rats. These results show that dietary DL-homocysteine has some regulatory effect on the two enzymes involved in the production of 'free' THF.
5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
Homocysteine compounds which influence the growth of a malignant neoplasm.
Since homocysteine metabolism is important in the control of normal and abnormal growth, three homocysteine derivatives were synthesized and tested for effects on the growth of transplanted murine adenocarcinoma. Arachidonoyl homocysteine thiolactone (HCT) amide decreased growth, and oleoyl HCT amide increased growth of the neoplasm. Pyridoxal HCT enamine decreased the growth of the neoplasm when given for 2 weeks prior to transplantation, but the compound had no effect when given after transplantation. The two inhibitory substances were tolerated well by normal mice except in high doses. These findings suggest an approach to prevention and therapy of human malignancy which utilizes homocysteine derivatives of normal biochemical constituents.
Adenocarcinoma↗
Isolation of folate-producing probiotic candidates and their effects on homocysteine metabolism and gut microbiota composition.
BACKGROUND: Folate deficiency is a global nutritional problem associated with multiple adverse health outcomes, including impaired one-carbon metabolism and elevated homocysteine levels (hyperhomocysteinemia). Gut microbiota-mediated folate biosynthesis has emerged as a promising strategy for improving the host's folate status. This study aimed to isolate folate-producing probiotic strains, clarify their folate synthesis mechanisms, and evaluate their regulatory effects on folate metabolism and gut microbiota. METHODS: High-throughput cultivation and screening were performed to isolate folate-producing candidate probiotics. Whole-genome sequencing analysis, pathway reconstruction, and metabolite profiling in fermented milk were performed to explore folate biosynthesis pathways and microbial cross-feeding interactions. A folate-deficient mouse model was established to evaluate the effects of a candidate probiotic cocktail on serum folate, homocysteine (Hcy) levels, and gut microbiota composition using quantitative PCR (qPCR) and 16S rRNA gene sequencing. RESULTS: High-throughput screening identified 8 high-folate-producing candidate probiotic strains, including Lactiplantibacillus plantarum and Heyndrickxia coagulans, from over 1,000 isolates. Genomic analysis revealed that most commonly used probiotics lacked para-aminobenzoic acid (pABA) biosynthesis genes but retained downstream modules, suggesting a reliance on cross-feeding with pABA-producing gut commensals such as Bacteroides. Metabolite profiling of fermented milk demonstrated that selected strains significantly increased bioactive 5-methyltetrahydrofolate (5-MeTHF) and tetrahydrofolate levels. In vivo, only a high-dose candidate probiotic cocktail significantly elevated serum folate (p < 0.05) and reduced homocysteine levels (p < 0.05) in deficient mice. Fecal qPCR confirmed dose-dependent transient persistence of the administered bacterial species. Consistent with the qPCR data, 16S rRNA gene sequences demonstrated significant enrichment of these administered species observed in the high-dose group. Furthermore, beta-diversity analysis found that high-dose candidate probiotic supplementation promoted a shift in the gut microbiota composition toward a normal profile, partially mitigating the dysbiosis induced by the folate-deficient diet. This effect was accompanied by a significant enrichment of potential short-chain fatty acid producers (e.g., Lachnospiraceae and Oscillospiraceae) and the depletion of potential opportunistic pathogens. CONCLUSION: This study screened high-folate-producing candidate probiotic strains and demonstrated their ability to synthesize the active form of 5-MeTHF. Moreover, folate-producing candidate probiotic cocktail treatment significantly improved folate status and Hcy metabolism and modulated the gut microbiota by enriching potential beneficial bacterial taxa. These findings suggested that folate-producing probiotics may serve as a promising microbiota-based strategy to improve folate availability and homocysteine metabolism.
B vitamin↗
[Effect of S-nucleosyl-L-homocysteines on the activity of DNA methylases].
It was studied effect of S-adenosyl, -uridyl, -citidyl and -inosyl homocysteines on activity of bacterial adenine and cytosine methylases from E. coli CK as well as on guanine methylase specific for DDVI phage. S-adenosyl homocysteine was shown to be the strong inhibitor of methylation; 10 micrometer of the substance inhibited all the enzymes studied by 98--99%. Use of total enzymatic preparations did not enable to find a difference in affinity of S-uridyl, -citidyl, and -inosyl homocysteines to various DNA methylases studied. All these preparations inhibited DNA methylases by 55--65%. Increase in concentration of inhibitor up to 20 micrometer did not elevate the inhibitory effect. Action of S-nucleosyl homocysteines did not depend on the type of acceptory DNA.
Coliphages↗
Methionine requirement and replacement by homocysteine in tissue cultures of selected rodent and human malignant and normal cells.
An absolute methionine requirement for cell growth in culture was observed in four experimental rodent neoplasms, namely, P815/ara-C, L1210, lymphoma 5178Y, and Walker 256. Normal human fibroblast (F-136-35-56) and the human malignant cell lines HeLa and mammary adenocarcinoma (AlAb) cells in culture showed equal growth in 0.1 mM L-methionine or 0.1 to 0.4 mM DL-homocysteine. A human pancreas adenocarcinoma (Capan-1) had somewhat more stringent requirements for DL-homocysteine, whereas a human lung adenocarcinoma (A-549) responded poorly, and a human acute lymphoblastic leukemia (CCRF-HSB-2) responded not at all to equimolar or excess DL-homocysteine in the absence of L-methionine. These differences in requirement for methionine and the ability or inability to replace methionine by homocysteine indicate that a general discrimination between benign and malignant tissues on the grounds of their methionine requirement is not possible for human cells.
Animals↗
Cytochemical detection of homocysteine in pernicious anemia and in chronic erythremic myelosis.
Utilizing a unique ability of homocysteine to form a yellow-brown precipitate with nickel chloride, a cytochemical test was developed in an effort to identify this amino acid. Among a variety of types of anemias studied, bright yellow-colored erythrocytes and erythroid precursors were found only in marrows from patients who had untreated pernicious anemia and chronic erythremic myelosis. The results of the study support the "methyltetrahydrofolate-trap" hypothesis in vitamin B12 deficiency, in which decreased activity of the methylocobalamin-dependent methyltransferase enzyme is believed to lead to accumulation of methyltetrahydrofolate and homocysteine in the deficient cells. The findings also raise the possibility that similar intracellular accumulations of homocysteine may occur in chronic erythremic myelosis, perhaps as a result of a defect in the methyltransferase enzyme.
5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
Cerebral metabolic and circulatory changes in the rat during sustained seizures induced by DL-homocysteine.
Sustained, generalized seizure activity was induced in anaesthetized (70% N2O), paralyzed and artifically ventilated rats by i.p. DL-homocysteine thiolactone in a dose of 11 mmol/kg. Epileptic discharges in the EEG were accompanied by marked perturbation of tissue metabolites. There was a fall in phosphocreatine concentration to 40% of control but only moderate changes in adenine nucleotides, a marked rise in lactate concentration, and a pronounced increase in the lactate/pyruvate ratio. Excessive amounts of dihydroxyacetone phosphate (and glyceraldehyde phosphate) accumulated, indicating that depletion of NAD+ occurred. There was marked accumulation of ammonia, glutamine and alanine, and reduction in glutamate and aspartate concentrations. Administration of a subconvulsive dose of homocysteine (7.5 mmol/kg) gave rise to changes in ammonia and amino acids, qualitatively similar to those occurring during seizures. It is concluded that although changes in the metabolites of the energy reserve were mainly caused by the induced seizures, those affecting amino acid concentrations were significantly influenced by accumulation of ammonia, secondary to metabolism of injected homocysteine. Cerebral blood flow (CBF) and oxygen utilization (CMRO2) were measured during sustained seizures. CMRO2 rose to 150% of control, with a corresponding increase in CBF.
Amino Acids↗
The detection of cysteine-homocysteine mixed disulphide in plasma of normal fasting man.
Cysteine-homocysteine mixed disulphide, formed in the degradation of methionine, is detected routinely in the plasma of fasting patients homozygous for homocystinuria and in some obligate heteroxygotes. It has not hitherto been identified in the plasma of normal fasting man. Using a highly cross-linked resin with lithium citrate buffers on a JEOL. Amino Acid Analyser, we have detected the mixed disulphide in every one of the plasma samples from twenty normal fasting subjects. The mean concentration was 3.25 mumol/l (SD 0.85, N = 20), with a range of from 1.68 to 4.85 mumol/l. The other neutral and acidic amino acids were within the accepted normal range. The study shows that circulating homocysteine is normally not immediately transformed to cystathionine or remethylated to methionine; some combines with cysteine to form measurable amounts of mixed disulphide. Since homocysteine may produce endothelial damage, the present findings could be relevant to an understanding of the pathogenesis of vascular disease.
Adult↗
Sulphr containing amino acids in chronic renal failure with particular reference to homocystine and cysteine-homocysteine mixed disulphide.
We measured plasma sulphur amino acids in twenty-two patients with chronic renal failure and compared the findings with those obtained in twenty-two normal subjects. In fasting blood (08.00 hours) cysteine-homocysteine mixed disulphide was significantly increased in the renal patients, mean values (+/- SD) being 8.2 +/- 3.4 and 3.1 +/- 1.0 mumol/l respectively (P less than 0.001). The increase was positively correlated with reduced renal function, as assessed by serum creatinine (r = 0.62; P less than 0.01). Homocystine was detected in nineteen patients, the mean concentration (+/- SD) being 1.7 +/- 0.6 mumol/l; it was not found in any normal subject. Methionine levels were not different but there were significant increases in cystine (P less than 0.001) and taurine (P less than 0.05) in the patients. Similar values for these amino acids were found in a second blood sample drawn at 16.00 hours. Changes in the other neutral and acidic amino acids measured were in agreement with those reported in chronic azotaemia. We concluded that plasma levels of all the principal sulphur amino acids except methionine are elevated in chronic renal failure emphasizing the importance of the kidney in sulphur excretion. Prolonged accumulation of homocysteine and cysteine-homocysteine mixed disulphide may be relevant to the development of accelerated vascular disease in patients with chronic renal failure by producing endothelial damage.
Amino Acids, Sulfur↗
Diseases of sulphur metabolism: implications for the methionine-homocysteine cycle, and vitamin responsiveness.
Sixteen inherited human diseases are now recognized, affecting most of the major steps in sulphur metabolism. Studies of patients with three types of homocystinuria have demonstrated unequivocally the major role of cystathionine formation in degradation of homocysteine, and the importance of homocysteine remethylation. Methionine balance studies of normal subjects and of a sarcosine oxidase-deficient subject have shown the predominant role of creatine synthesis in methionine utilization and permitted assessment of the rate of oxidation of the methyl group of methionine. Together, the results demonstrate that once regulatory adjustments have been made the rate of methylneogensis is nicely controlled so that labile methyl groups are made available in amounts just sufficient to meet the needs for methionine. When excess methionine is ingested the four-carbon moiety is diverted into cystathionine, the methyl group is oxidized via sarcosine and the flow of partially oxidized one-carbon units is diverted away from 5-methyltetrahydrofolate toward CO2. Studies of cystathionine synthase-deficient patients demonstrate that the capacity to respond or not to respond to pyridoxine administration is genetically controlled, probably through structural differences in mutant cystathionine synthases. However, the properties of the enzyme crucial in conferring responsiveness have not yet been identified.
Adolescent↗
Binding capacities of various analogues of S-adenosyl-L-homocysteine to protein methyltransferase II from human erythrocytes.
A series of analogues of S-adenosyl-L-homocysteine, modified mainly in the amino acid portion of the molecule, have been synthesized. All were found to be competitive inhibitors of protein methyltransferase II from human erythrocytes. S-adenosyl-L-homocysteine remains however by far the most effective inhibitor of the methylase.
Erythrocytes↗
Potential inhibitors of S-adenosylmethionine-dependent methyltransferases. 7. Role of the ribosyl moiety in enzymatic binding of S-adenosyl-L-homocysteine and S-adenosyl-L-methionine.
A series of 2',3'-acyclic analogues of S-adenosyl-L-homocysteine were synthesized and evaluated as inhibitors of S-adenosyl-L-methionine-dependent methyltransferases. The 2',3'-acyclic analogues were prepared by periodate oxidation of the corresponding ribonucleosides, followed by reduction of the intermediate dialdehydes with sodium borohydride. These 2',3'-acyclic ribonucleosides were inactive as inhibitors of histamine N-methyltransferase, catechol O-methyltransferase, phenylethanolamine N-methyltransferase, and hydroxyindole O-methyltransferase. These results suggest that the rigidity of the ribosyl ring of S-adenosyl-L-homocysteine is crucial to its enzymatic bindings.
Animals↗
Cysteine-homocysteine mixed disulphide: differing plasma concentrations in normal men and women.
1. The mixed disulphide of cysteine and homocysteine is known always to be present in the plasma of patients with homocystinuria, an abnormality of methionine metabolism. Recently we have shown that it is also detectable in low concentration in the plasma of normal fasting man. In the present study we measured mixed disulphide concentrations after an overnight fast in 24 normal men and compared the findings with those obtained in 24 normal premenopausal women of similar age. 2. The mean value for men (+/- SD) of 3.3 +/- 0.8 micromol/l was significantly higher than that for women (2.4 +/- 0.7 micromol/l; P less than 0.001). Of the other neutral and acidic amino acids measured mean values for leucine, isoleucine and valine (P less than 0.001) and cystine (P less than 0.01) were also higher in the men but methionine concentrations were not significantly different. 3. The higher branched-chain amino acid concentrations in men could be related to larger muscle bulk and protein intake, but the higher cysteine-homocysteine mixed disulphide concentrations are consistent with differences in methionine metabolism between men and women under the age of 50 years.
Adult↗
The effect of homocysteine, methionine, serine and glycine on DNA synthesis by human normoblastic and megaloblastic bone marrow cells.
Both glycine and methionine, when added to a suspension of human bone marrow cells, impaired the utilization of deoxyuridine for DNA synthesis, using either the uptake of 3H-deoxyuridine or the subsequent uptake of 3H-thymidine as an index. Homocysteine reduced the uptake of both 3H-deoxyuridine and 3H-thymidine, indicating interference with DNA synthesis after the stage of thymidylate synthesis. Another explanation that the decreased uptake of both substances by homocysteine was due to cell damage caused in vitro was suggested by the trypan blue viability test. Serine generally did not produce significant effects. No difference could be detected between the results in normoblastic and megaloblastic marrow.
Bone Marrow Cells↗
Deficiency of S-adenosylmethionine-homocysteine methyltransferase activity in hepatoma cells.
S-Adenosylmethionine-homocysteine methyltransferase, which catalyzes synthesis of methionine from homocysteine, with the use of S-adenosylmethionine as the methyl donor, is absent in tumor tissue such as rat ascites hepatoma and Morris hepatoma but is present in rat liver homogenate. Absence of the enzymatic activity in tumor cells is not due to the action of an inhibitor. S-Adenosylhomocysteine hydrolase, however, is present in both rat liver and hepatoma tissue.
Animals↗