Metabolism Of Sulfur-containing Amino Acids Research Articles

The reverse transsulfuration pathway affects the colonic microbiota and contributes to colitis in mice

Cystathionine γ-lyase (CTH) is a critical enzyme in the reverse transsulfuration pathway, the major route for the metabolism of sulfur-containing amino acids, notably converting cystathionine to cysteine. We reported that CTH supports gastritis induced by the pathogen Helicobacter pylori. Herein our aim was to investigate the role of CTH in colonic inflammation. First, we found that CTH is induced in the colon mucosa in mice with dextran sulfate sodium-induced colitis. Expression of CTH was completely absent in the colon of Cth–/– mice. We observed that clinical and histological parameters are ameliorated in Cth-deficient mice compared to wild-type animals. However, Cth deletion had no effect on tumorigenesis and the level of dysplasia in mice treated with azoxymethane-DSS, as a reliable model of colitis-associated carcinogenesis. Mechanistically, we determined that the deletion of the gene Slc7a11 encoding for solute carrier family 7 member 11, the transporter of the anionic form of cysteine, does not affect DSS colitis. Lastly, we found that the richness and diversity of the fecal microbiota were significantly increased in Cth–/– mice compared to both WT and Slc7a11–/– mice. In conclusion, our data suggest that the enzyme CTH represents a target for clinical intervention in patients with inflammatory bowel disease, potentially by beneficially reshaping the composition of the gut microbiota.

Exploring the possible mechanisms of X-rays treatment for retention aroma volatiles in shiitake mushrooms during low temperature storage

X-rays irradiation has been demonstrated to effectively preserve the freshness of edible fungi and delay the loss of aroma during storage. In this study, shiitake mushrooms were irradiated with X-rays dose of 0.5 kGy and stored at 2 °C for 35 days. Non-irradiated mushrooms were recorded as control group. Results indicated that 0.5 kGy X-rays treatment preserved the flavor quality by exhibiting higher volatile substance content in shiitake mushrooms. X-rays treatment promoted the activities of lipoxygenase (LOX) and alcohol dehydrogenase (ADH) and oxidation of linoleic acid. In addition, the degradation of methionine and cysteine was facilitated by X-rays. Higher enzymes activities for γ-glutamyl transpeptidase (GGT) and cystine sulfoxide lyase (CS lyase) were found in 0.5 kGy X-rays irradiated mushrooms. These findings suggest that the retention of mushroom flavor by X-rays treatment is closely related to fatty acid metabolism, sulfur-containing amino acid metabolism, and lentinic acid metabolism.

Effects of dietary methionine and taurine interaction on growth performance, the profiles of amino acids, and protein metabolism of Chinese mitten crab, Eriocheir sinensis

The purpose of this study is to explore the interaction between dietary methionine and taurine levels on growth performance, the profiles of amino acids, protein metabolism, and how taurine spares methionine of Chinese mitten crab (Eriocheir sinensis). The crabs were divided into six groups which were fed six diets formulated with two Tau levels (0 and 0.4%) and three Met levels (0.6%, 0.9% and 1.2%). The results showed that the weight gain rate and specific growth rate were the highest in the crabs fed 0.4% Tau and 0.6% Met. Crabs fed 1.2% Met had the highest survival rate and lowest feed conversion ratio. Furthermore, the hepatopancreas and muscle amino acid content were significantly influenced by the interactive effects of Met and Tau (P < 0.05). Moreover, interactive effects of dietary methionine and taurine were significantly observed in the expressions of amino acid metabolism-related genes (P < 0.05). Additionally, crabs fed 1.2% Met and 0% Tau had the highest activities of cysteine decarboxylase (CSD) and cysteine dioxygenase (CDO). In conclusion, the addition of appropriate amount of taurine to the diet can reduce the requirement of methionine for Chinese mitten crab by regulating the activities of CSD and CDO. At the same time, the addition of methionine and taurine could affect the amino acids metabolism. Therefore, the diet formula of Chinese mitten crab needs to consider the metabolism of sulfur-containing amino acids.

Does the Micronutrient Molybdenum Have a Role in Gestational Complications and Placental Health?

Molybdenum is an essential trace element for human health and survival, with molybdenum-containing enzymes catalysing multiple reactions in the metabolism of purines, aldehydes, and sulfur-containing amino acids. Recommended daily intakes vary globally, with molybdenum primarily sourced through the diet, and supplementation is not common. Although the benefits of molybdenum as an anti-diabetic and antioxidant inducer have been reported in the literature, there are conflicting data on the benefits of molybdenum for chronic diseases. Overexposure and deficiency can result in adverse health outcomes and mortality, although physiological doses remain largely unexplored in relation to human health. The lack of knowledge surrounding molybdenum intake and the role it plays in physiology is compounded during pregnancy. As pregnancy progresses, micronutrient demand increases, and diet is an established factor in programming gestational outcomes and maternal health. This review summarises the current literature concerning varied recommendations on molybdenum intake, the role of molybdenum and molybdoenzymes in physiology, and the contribution these play in gestational outcomes.

Diagnosis and treatment of orphan disease — homocystinuria and megaloblastic anemia, type cblG

The term «homocystinuria» combines a number of genetically determined nosological forms caused by defects of the metabolism of sulfur-containing amino acids (methionine, homocysteine), cobalamin and folate. The group of these diseases includes «classical» homocystinuria caused by insufficiency of cystathionine beta-synthase and forms associated with defects in methionine remethylation processes. More information is given about one of these forms — homocystinuria and megaloblastic anemia, type cblG, caused by MTR gene mutations. The results of observation of a child with this disease are presented. The clinical status includes: intellectual disability, autistic behavioral traits, stereotypes, nystagmus, visual impairment, macrocytic anemia, epilepsy in remission. Effective treatment requires the use of medications not registered in the Russian Federation — betaine and hydroxocobalamin.

Tryptophan pretreatment adjusts transcriptome and metabolome profiles to alleviate cadmium toxicity in Arabidopsis

Cadmium (Cd) is highly toxic to all organisms including plants, and recently tryptophan (Trp) pretreatment of plant seedlings is shown to improve Cd tolerance. But the underlying mechanism remains largely unknown. In this study, we used Arabidopsis (Arabidopsis thaliana) to determine the physiological relevance of Trp pretreatment in alleviating Cd toxicity in plants and explore its molecular mechanism with a focus on the metabolic pathways. The results showed that Trp pretreatment maintained the biomass and root lengths, relieved Cd-induced lipid peroxidation, and reduced Cd transport to the shoots, and eventually improved the response against Cd in Arabidopsis seedlings. The integrative analyses of the transcriptome and metabolome further revealed that Trp pretreatment alleviated Cd toxicity not only through a known mechanism of producing a major auxin indole-3-acetic acid and maintaining its levels, but also through two previously unrecognized mechanisms: increasing the area and strength of cell walls by promoting lignification to further reduce Cd entry, and fine-tuning Cd detoxification products derived from sulfur-containing amino acid metabolism. Our findings thereby provide deep mechanical insights into how Trp alleviates Cd toxicity in plants.

Alpha-Tocopherol from People to Plants Is an Essential Cog in the Metabolic Machinery.

Significance: Protection from oxygen, a diradical, became a necessity with the evolution of photosynthetic organisms about 2.7 billion years. α-Tocopherol plays an essential, protective role in organisms from plants to people. An overview of human conditions that result in severe vitamin E (α-tocopherol) deficiency is provided. Recent Advances: α-Tocopherol has a critical role in the oxygen protection system by stopping lipid peroxidation, its induced damage, and cellular death by ferroptosis. Recent findings in bacteria and plants support the concept of why lipid peroxidation is so dangerous to life and why the family of tocochromanols are essential for aerobic organisms and for plants. Critical Issues: The hypothesis that prevention of the propagation of lipid peroxidation is the basis for the α-tocopherol requirement in vertebrates is proposed and further that its absence dysregulates energy metabolism, one-carbon metabolism, and thiol homeostasis. By recruiting intermediate metabolites from adjacent pathways to sustain effective lipid hydroperoxide elimination, α-tocopherol function is linked not only to NADPH metabolism and its formation through the pentose phosphate pathway via glucose metabolism but also to sulfur-containing amino acid metabolism and to one-carbon metabolism. Future Directions: Evidence from humans, animals, and plants supports the hypothesis, but future studies are needed to assess the genetic sensors that detect lipid peroxidation and cause the ensuing metabolic dysregulation. Antioxid. Redox Signal. 38, 775-791.

Prospects for the sulfur-containing amino acids medicines usage for trimethylamine-N-oxide biosynthesis modulation in humans

The aim: to identify prospects for the sulfur-containing amino acids medicines usage for trimethylamine oxide (TMAO) biosynthesis modulation in humans. Intestinal microbiome and its metabolic products are currently widely discussed as a new therapeutic target for the treatment of cardiovascular, neurological and metabolic diseases. The effect of the intestinal microbiome on human health is unconditional. Its metabolites, including trimethylamine (TMA), TMAO and plasma amino acids, play an important role in the mechanisms of many diseases. The synthesis of TMAO directly depends on such factors as diet, intestinal microbiome status, genetic characteristics of the human body (activity and type of hepatic flavin monooxygenase). At the same time, all these factors are also able to affect the metabolism of sulfur-containing amino acids in the human body. Conversely, sulfur-containing amino acids are able to simulate the state of the intestinal microbiome and the activity of hepatic flavin monooxygenase. Today many sulfur-containing amino acid drugs are widely used in therapeutic practice (taurine, methionine, glutathione), including for the cardiovascular and metabolic diseases treatment. Their effect on the state of the intestinal microbiome and its metabolites is still unexplored. There are currently no strong clinical studies for the use of amino acid preparations to reduce plasma TMAO levels, although this perspective is interesting. The possibility of using taurine is questionable as it affects the state of the intestinal microbiome in ultra-high doses (more than 3 g/day), which can cause side effects. Glutathione drugs have low bioavailability due to its physical and chemical properties, and therefore have not become widespread in therapeutic practice. Drugs that activate glutathione synthesis – for example, selenium derivatives, glutoredoxins, some heat shock proteins (HPS70) actions are not studied in vivo enough. Unfortunately, methionine preparations, on the other hand, increase plasma TMAO levels. Conclusions. Despite the deep pathogenetic affinity of sulfur-containing amino acids and TMAO synthesis, the prospect of using these amino acids drugs to reduce TMAO synthesis is questionable. The problem of reducing the synthesis of TMAO in the human body remains unsolved and requires further search for promising pathogenetically drugs for its correction.

Methionine and total homocysteine in hypertensive patients with renal excretory dysfunction.

The role of the kidneys in the metabolism and homeostasis of sulfur-containing amino acids is great, so the levels of methionine (Met), total homocysteine (tHcy) and their ratios can be of diagnostic value in chronic kidney disease (CKD), in a course of the arterial hypertension (AH). The aim of the study was to evaluate the Met/tHcy ratio in hypertensive patients with CKD. We used blood plasma of 76 patients aged 40-75 years with AH and the excretory dysfunction of the kidneys; subgroups: 1 - with proteinuria (n=37); 2 - without proteinuria with glomerular filtration rate (GFR) < 90 ml/min/1.73 m2 (n=39) and comparison group 3 - patients with AH without renal excretory dysfunction (n=28). Significantly lower Met levels were in subgroup 1. THcy levels were higher in subgroups 1 and 2 than in group 3. The Met/tHcy ratio revealed differences in subgroups 1 and 2 vs group 3. No differences were found in Arg and Lys levels. Positive correlations of the Met/tHcy ratio with the number of erythrocytes, but not with the level of hemoglobin, were revealed. In the ROC analysis, the cut-off points for the Met/tHcy ratio compared to group 3 were 3.08 for subgroup 1 and 3.36 for subgroup 2. With the progression of CKD, there is an increase in the levels of tHcy in the blood, and a decrease in the content of Met. A decrease in GFR, especially in a case with proteinuria, is accompanied by a decrease in the level of Met. The Met/tHcy ratio above 3.36 can be considered as the minimum of the balance between these sulfur-containing amino acids contents in a blood necessary for hypertensive patients with CKD.

Comparative analysis of the mineral composition of the&#x0D; leukocyte, erythrocyte fraction and PRP plasma in patients with bisphosphonate osteonecrosis of the jaw bones

A complication of the use of bisphosphonate drugs is the development of bisphosphonate osteonecrosis. There is not enough information about the state of the microelement composition of the blood and the dynamics of metabolic processes for various bisphosphonate drugs. There are 184 patients under observation for bisphosphonate osteonecrosis of the jaw bones. The mineral components of three blood fractions were monitored: sulfur (S2-), chlorine (Cl-), potassium (K+), calcium (Ca2+), phosphorus (P3+) at the preoperative and postoperative stages. At the preoperative stage, the negative dynamics of indicators of bone metabolites (Ca2+ and P3+) contributed to the development of osteomalacia, followed by a jaw fracture due to local loads. Hypercalcemia developed against the background of acidosis in the bone tissue (Ca2+ ions were replaced by H+ ions, with partial diffusion into the liquid fraction, due to disorganization of the synthesis of chondroitinsulfuric acid). Hyperphosphatemia is due to the pharmacokinetics of bisphosphonate drugs. Violation of the metabolism of sulfur-containing amino acids leads to the accumulation of S2- in blood fractions. The decrease in Cl- is due to metabolic acidosis against the background of an atrabiliary gas exchange function of erythrocytes, which enhances the pathological focus of tissues with the migration of Cl- to the lesion. A decrease in K+ was noted against the background of severe muscle atony. The dynamics of the studied parameters correlates with the clinical picture of bisphosphonate osteonecrosis. The trace element composition of blood fractions, starting from the 7th day of the postoperative period, was characterized by a trend towards positive dynamics. With further observation at the 3rd and 6th months, the content of the studied trace elements in the reference values. The clinical picture corresponds to the scope and timing of surgery in 100% of patients.

Effects of dietary restriction on hepatic sulfur-containing amino acid metabolism and its significance in acetaminophen-induced liver injury

Dietary restriction (DR) has been revealed to have health benefits as it induces reduction in oxidative stress. Glutathione (GSH), an important cellular antioxidant, is increased in rodent livers owing to DR; however, the exact mechanism and clinical relevance of DR are yet to be fully understood. In this study, male C57BL/6 mice were administered a 50% restricted diet for 7 d, and the hepatic sulfur-containing amino acid (SAA) metabolism was determined to assess the biosynthesis of GSH. The hepatic methionine level was found to decrease, while the homocysteine, cysteine, and GSH levels were increased owing to decreased betaine-homocysteine methyltransferase (BHMT) and increased CβS, CγL, and glutamate cysteine ligase catalytic subunit (GCLC) proteins in the livers of mice subjected to DR. To determine the effects of DR on drug-induced oxidative liver injury, mice subjected to DR were injected with a toxic dose (300 mg/kg) of acetaminophen (APAP). DR significantly alleviated APAP-induced liver damage and oxidative stress, which might be attributed to the higher levels of GSH and related antioxidant enzyme (GPx, GSTα, and GSTµ) in the livers. The decrease in the levels of hepatic CYP1A, 2E1, and 3A, which imply the inhibition of APAP metabolic activation, could contribute to the lower hepatotoxicity in mice subjected to DR. Overall, our findings revealed that DR stimulated the hepatic transsulfuration pathway and GSH synthesis. The consequent elevation of GSH could thus serve as an important mechanism of DR-mediated liver protection against APAP intoxication.

Synergistic effects of dietary methionine and taurine on growth performance, blood parameters, expression in hepatic sulfur-metabolism genes, and flesh quality of large Nile tilapia

This study aimed to evaluate the growth performance, expression of genes related to the metabolism of sulfur-containing amino acids, and flesh quality of large Nile tilapia (Oreochromis niloticus). Fish (n = 120; 1199 ± 46 g) were randomly distributed into four groups and each fish group was hand-fed a basal diet not supplemented (CON) or supplemented with methionine (MET), taurine (TAU), and methionine and taurine (MET+TAU) until apparent satiety for seven weeks. Compared to CON group, the fish group on the MET diet experienced increased in final body weight, protein retention efficiency, and fillet yield by 62.83 g, 9.82%, and 1.31%, respectively (p < 0.05). These results were linked to the down-regulation of cystathionine β-synthase (CBS) and cysteine dioxygenase (CDO) gene controlled by methionine supplementation. Moreover, up-regulation of the adenosylhomocysteine (AHCY) gene in fish offered TAU diet as a metabolic response to methionine deprivation. Furthermore, taurine prevented color deterioration and increased fillet hardness and chewiness attributes as compared to CON group (p < 0.05). Overall, this study indicated a marked effect of dietary methionine on growth performance, particularly fillet yield, and notable synergic effect of methionine and taurine preventing color deterioration and increasing fillet hardness.

Sulfite may disrupt estrogen homeostasis in human via inhibition of steroid arylsulfatase.

Steroid arylsulfatase is an important enzyme in human, which plays an important role in dynamic equilibrium of natural estrogens. On the other hand, sulfite can be endogenously produced as a consequence of human body's metabolism of sulfur-containing amino acids, while its main sources to human are mainly derived from food as it is a widely used additive. Sulfite-sensitivity is a well-known phenomenon to a small proportion of populations. However, its potential adverse effects on healthy individuals have been hardly reported. It was for the first time reported in this study that sulfite could effectively inhibit arylsulfatase, and its IC50 values for the snail- and human urine-derived arylsulfatase were determined to be 71.9 and 142.8µM, which were lower than the concentration of sulfite in some healthy population. Consequently, it appears that sulfite might disrupt estrogen homeostasis in human, and this deserves further investigation.

Folate cycle genetics, level of homocysteine, thyroid and pituitary hormones in the blood among the children from the districts bordering the Chornobyl exclusion zone

Objective: The aim of the study was to identify interrelations between the state of folate cycle genetic apparatus and blood levels of homocysteine, thyroid and adenohypophysis hormones in the blood among the children from Ivankivskyi and Poliskyi districts, Kyiv region, bordering the Chornobyl exclusion zone (СhEZ). Methods: Immunochemical, genetic, statistical ones. Results: We measured blood levels of homocysteine (Hcy), pituitary thyroid-stimulating hormone (TSH), free triiodothyronine (T3), free thyroxine (T4) in 158 children from Poliskyi district and 178 children from Ivankivskyi district and assessed the state of a genetic system of the folate cycle (FC). The average age of the examined was (15.2 ± 0.9) years old (95% CI 15.0-15.4 years old). Taking into account the FC genotypes, genetic subgroups were formed, they were based on 100% representation of one specific genotype. The laboratory examination was carried out twice: in April and December 2015 (before and after the fires in the ChEZ). It was found out that in the total group of the children, as well as in most of analyzed genetic subgroups, the level of Hcy and thyroid hormones (TG) in the children from Ivankivskyi district was statistically significantly higher than in those from Poliskyi district. At the same time, a direct association between Hcy and TSH was observed in the total group, as well as in most of the genetic subgroups of children from Ivankivskyi district, and this ssociation was absent in the children from Poliskyi district. The blood level of Hcy both in the children from Poliskyi district and in the children from Ivankivskyi district was statistically significantly higher in the subgroup containing only homozygous variants of the T allele of the MTHFR:677 genetic polymorphism in comparison with the subgroups containing neutral C alleles of the same polymorphism. At the same time, there were no differences for TSH, T3 and T4. Сonclusions: The analysis enabled to establish a synchronous reaction of metabolic cycles ensuring the metabolism of Hcy and thyroid hormones in the adolescents, regardless of the FC genotypes. Correlation analysis, as well as the results of statistical analysis, indicate that an increase in the level of Hcy in the blood of children induced the synthesis of TSH and T3. The results show a close relationship between thyroid hormone genesis and the metabolism of methionine sulfur-containing amino acids and Hcy. A forest fire, containing long-lived radioactive elements, is the most likely reason for the increase of Hcy level and, as a result, the hormones of the pituitary-thyroid axis in the blood of the children living in the districts, bordering the ChEZ.

Peculiarities of glutathione metabolism in COVID-19

The article presents the results of studies on the effect of coronavirus infection on the metabolism of glutathione and sulfur-containing amino acids in patients with COVID-19. The defeat of the pulmonary system by the COVID-19 virus is accompanied by hypoxia, which provokes an increased excretion of cystine in the urine, which can cause tension in the metabolism of sulfur-containing amino acids and glutathione. The understanding of the mechanisms of influence of the COVID-19 virus on metabolic processes in the body has been expanded

Neuroprotective Roles of the Reverse Transsulfuration Pathway in Alzheimer’s Disease

The reverse transsulfuration pathway has emerged as a central hub that integrates the metabolism of sulfur-containing amino acids and redox homeostasis. Transsulfuration involves the transfer of sulfur from homocysteine to cysteine. Cysteine serves as the precursor for several sulfur-containing molecules, which play diverse roles in cellular processes. Recent evidence shows that disruption of the flux through the pathway has deleterious consequences. In this review article, I will discuss the actions and regulation of the reverse transsulfuration pathway and its links to other metabolic pathways, which are disrupted in Alzheimer’s disease (AD). The potential nodes of therapeutic intervention are also discussed, which may pave the way for the development of novel treatments.

16 Sulfur amino acid utilization during immune system stimulation in growing pigs

Abstract Immune system stimulation (ISS) modifies protein and amino acid (AA) metabolism in animals and humans. During ISS, AA are redirected away from growth and reproduction towards mounting an immune response. This redirection can impact AA requirements both qualitatively (i.e., the AA ratio) and quantitatively. Special attention has been given to sulfur-containing amino acid (SAA; Met + Cys) metabolism during ISS, due to their roles as precursors for the synthesis of proteins and metabolites that are involved in the immune response. A series of studies were conducted to investigate the impact of ISS on various aspects of SAA utilization, including ileal digestibility, plasma kinetics, the glutathione (GSH) synthesis rate, the irreversible loss of Cys, and dietary total SAA requirements. In all of the studies, pigs were feed restricted (≥ 2 times the maintenance requirement for ME) to eliminate the confounding effect of ISS on feed intake. Results indicated that ISS alters SAA metabolism and increases SAA requirements per unit of protein deposition. The latter occurs due to increased maintenance requirements for SAA during ISS. The results also showed that the enhanced maintenance requirement for SAA occurs mainly as a result of increased SAA utilization, mainly Cys, for the synthesis of immune system metabolites, such as GSH and acute-phase proteins, as well as the increased catabolism of Cys to taurine. In addition, we found that ISS increases the dietary Met-to-total SAA ratio in pigs, suggesting an enhanced preferential demand for dietary Met during ISS, perhaps to support an elevated rate of transsulfuration. Collectively, our findings point toward a need for developing an optimal dietary AA profile for diseased pigs.

Lessons Learned from Inherited Metabolic Disorders of Sulfur-Containing Amino Acids Metabolism

The metabolism of sulfur-containing amino acids (SAAs) requires an orchestrated interplay among several dozen enzymes and transporters, and an adequate dietary intake of methionine (Met), cysteine (Cys), and B vitamins. Known human genetic disorders are due to defects in Met demethylation, homocysteine (Hcy) remethylation, or cobalamin and folate metabolism, in Hcy transsulfuration, and Cys and hydrogen sulfide (H2S) catabolism. These disorders may manifest between the newborn period and late adulthood by a combination of neuropsychiatric abnormalities, thromboembolism, megaloblastic anemia, hepatopathy, myopathy, and bone and connective tissue abnormalities. Biochemical features include metabolite deficiencies (e.g. Met, S-adenosylmethionine (AdoMet), intermediates in 1-carbon metabolism, Cys, or glutathione) and/or their accumulation (e.g. S-adenosylhomocysteine, Hcy, H2S, or sulfite). Treatment should be started as early as possible and may include a low-protein/low-Met diet with Cys-enriched amino acid supplements, pharmacological doses of B vitamins, betaine to stimulate Hcy remethylation, the provision of N-acetylcysteine or AdoMet, or experimental approaches such as liver transplantation or enzyme replacement therapy. In several disorders, patients are exposed to long-term markedly elevated Met concentrations. Although these conditions may inform on Met toxicity, interpretation is difficult due to the presence of additional metabolic changes. Two disorders seem to exhibit Met-associated toxicity in the brain. An increased risk of demyelination in patients with Met adenosyltransferase I/III (MATI/III) deficiency due to biallelic mutations in the MATIA gene has been attributed to very high blood Met concentrations (typically >800μmol/L) and possibly also to decreased liver AdoMet synthesis. An excessively high Met concentration in some patients with cystathionine β-synthase deficiency has been associated with encephalopathy and brain edema, and direct toxicity of Met has been postulated. In summary, studies in patients with various disorders of SAA metabolism showed complex metabolic changes with distant cellular consequences, most of which are not attributable to direct Met toxicity.

Metabolism of Sulfur-Containing Amino Acids: How the Body Copes with Excess Methionine, Cysteine, and Sulfide

Metabolism of excess methionine (Met) to homocysteine (Hcy) by transmethylation is facilitated by the expression of methionine adenosyltransferase (MAT) I/III and glycine N-methyltransferase (GNMT) in liver, and a lack of either enzyme results in hypermethioninemia despite normal concentrations of MATII and methyltransferases other than GNMT. The further metabolism of Hcy by the transsulfuration pathway is facilitated by activation of cystathionine β-synthase (CBS) by S-adenosylmethionine (SAM) as well as the relatively high KM of CBS for Hcy. Transmethylation plus transsulfuration effects catabolism of the Met molecule along with transfer of the sulfur atom of Met to serine to synthesize cysteine (Cys). Oxidation and excretion of Met sulfur depend upon Cys catabolism and sulfur oxidation pathways. Excess Cys is oxidized by cysteine dioxygenase 1 (CDO1) and further metabolized to taurine or sulfate. Some Cys is normally metabolized by desulfhydration pathways, and the hydrogen sulfide (H2S) produced is further oxidized to sulfate. If Cys or Hcy concentrations are elevated, Cys or Hcy desulfhydration can result in excess H2S and thiosulfate production. Excess Cys or Met may also promote their limited metabolism by transamination pathways.

Identification and characterization of a sulfite reductase gene and new insights regarding the sulfur-containing amino acid metabolism in the basidiomycetous yeast Cryptococcus neoformans.

The amino acid biosynthetic pathway of invasive pathogenic fungi has been studied as a potential antifungal drug target. Studies of the disruption of genes involved in amino acid biosynthesis have demonstrated the importance of this pathway in the virulence of Cryptococcus neoformans. Here, we identified the MET5 (CNL05500) and MET10 (CNG03990) genes in this pathway, both encoding sulfite reductase, which catalyzes the reduction of sulfite to sulfide. The MET14 (CNE03880) gene was also identified, which is responsible for the conversion of sulfate to sulfite. The use of cysteine as a sulfur source led to the production of methionine via hydrogen sulfide synthesis mediated by CYS4 (CNA06170), CYS3 (CNN01730), and MST1 (CND03690). MST1 exhibited high homology with the TUM1 gene of Saccharomyces cerevisiae, which has functional similarity with the 3-mercaptopyruvate sulfurtransferase (3-MST) gene in humans. Although the hypothesis that hydrogen sulfide is produced from cysteine via CYS4, CYS3, and MST1 warrants further study, the new insight into the metabolic pathway of sulfur-containing amino acids in C. neoformans provided here indicates the usefulness of this system in the development of screening tools for antifungal drug agents.