Serine-glycine Metabolism Research Articles

Integrated application of transcriptomics and metabolomics provides insights into acute hepatopancreatic necrosis disease resistance of Pacific white shrimp Litopenaeus vannamei.

Acute hepatopancreatic necrosis disease (AHPND) has caused a huge economic loss to shrimp aquaculture. Vibrio parahaemolyticus (VpAHPND) is regarded as a major causative agent of AHPND in the Pacific white shrimp Litopenaeus vannamei. However, knowledge about how shrimp resist to AHPND is very limited. In order to learn the molecular mechanisms underlying AHPND resistance of shrimp, comparison between disease-resistant family and susceptible family of L. vannamei were performed at transcriptional and metabolic levels. Integrated analysis of transcriptomics and metabolomics on hepatopancreas of shrimp, the target tissue of VpAHPND, showed that significant differences existed between resistant family and susceptible family of shrimp. The susceptible family showed higher level of glycolysis, serine-glycine metabolism, purine and pyrimidine metabolism, but lower level of betaine-homocysteine metabolism in the hepatopancreas in comparison with the resistant family without VpAHPND infection. Curiously, VpAHPND infection induced up-regulation of glycolysis, serine-glycine metabolism, purine metabolism, pyrimidine metabolism, and pentose phosphate pathway, and down-regulation of betaine-homocysteine metabolism in resistant family. In addition, arachidonic acid metabolism and some immune pathways, like NF-κB and cAMP pathways, were up-regulated in the resistant family after VpAHPND infection. In contrast, amino acid catabolism boosted via PEPCK-mediated TCA cycle flux was activated in the susceptible family after VpAHPND infection. These differences in transcriptome and metabolome between resistant family and susceptible family might contribute to the resistance of shrimp to bacteria. IMPORTANCE Vibrio parahaemolyticus (VpAHPND) is a major aquatic pathogen causing acute hepatopancreatic necrosis disease (AHPND) and leads to a huge economic loss to shrimp aquaculture. Despite the recent development of controlling culture environment, disease resistant broodstock breeding is still a sustainable approach for aquatic disease control. Metabolic changes occurred during VpAHPND infection, but knowledge about the metabolism in resistance to AHPND is very limited. Integrated analysis of transcriptome and metabolome revealed the basal metabolic differences exhibited between disease-resistant and susceptible shrimp. Amino acid catabolism might contribute to the pathogenesis of VpAHPND and arachidonic acid metabolism might be responsible for the resistance phenotype. This study will help to enlighten the metabolic and molecular mechanisms underlying shrimp resistance to AHPND. Also, the key genes and metabolites of amino acid and arachidonic acid pathway identified in this study will be applied for disease resistance improvement in the shrimp culture industry.

Understanding The Regulatory Role of USP32 and SHMT2 in The Progression of Gastric Cancer.

Gastric cancer is the fifth most common neoplasm and the fourth reason for mortality globally. Incidence rates are highly variable and dependent on risk factors, epidemiologic and carcinogenesis patterns. Previous studies reported that Helicobacter pylori (H. pylori) infection is one the strongest known risk factor for gastric cancer. USP32 is a deubiquitinating enzyme identified as a potential factor associated with tumor progression and a key player in cancer development. On the other hand, SHMT2 is involved in serine-glycine metabolism to support cancer cell proliferation. Both USP32 and SHMT2 are reported to be upregulated in many cancer types, including gastric cancer, but its complete mechanism is not fully explored yet. The present study explored possible mechanism of action of USP32 and SHMT2 in the progression of gastric cancer. In this experimental study, Capsaicin (0.3 g/kg/day) and H. pylori infection combination was used to successfully initiate gastric cancer conditions in mice. It was followed by 40 and 70 days of treatment to establish initial and advanced conditions of gastric cancer. Histopathology confirmed formation of signet ring cell and initiation of cellular proliferation in the initial gastric cancer. More proliferative cells were also observed. In addition, tissue hardening was confirmed in the advanced stage of gastric cancer. USP32 and SHMT2 showed progressive upregulated expression, as gastric cancer progress. Immunohistologically, it showed signals in abnormal cells and high-intensity signals in the advanced stage of cancer. In USP32 silenced tissue, expression of SHMT2 was completely blocked and reverted cancer development as evident with less abnormal cell in initial gastric cancer. Reduction of SHMT2 level to one-fourth was observed in the advanced gastric cancer stages of USP32 silenced tissue. USP32 had a direct role in regulating SHMT2 expression, which attracted therapeutic target for future treatment.

Target enzymes in serine-glycine-one-carbon metabolic pathway for cancer therapy.

Cancer cells selectively take up exogenous serine or synthesize serine via the serine synthesis pathway for conversion into intracellular glycine and one-carbon units for nucleotide biosynthesis. In this process, serine-glycine metabolism and the one-carbon cycle play vital roles, which is named serine-glycine-one-carbon metabolism (SGOC). The SGOC pathway is a metabolic network crucial for tumorigenesis with unexpected complexity and clinical importance. Accumulating evidence has demonstrated that metabolic enzymes in SGOC metabolism play key roles in tumorigenesis, metastasis and resistance to therapies. In this review, we focus on the involvement of serine and glycine in the folate-mediated one-carbon pathway during cancer progression and highlight the pathways through which cancer cells acquire and use one-carbon units. In addition, we discuss the recently elucidated effects of SGOC (folate cycle) metabolic enzymes in the occurrence and development of tumors and their links to drug resistance. Inhibitors of target enzymes in the SGOC pathway display promise as investigational new drug candidates for the treatment of tumors.

SHMT2 Drives the Progression of Colorectal Cancer by Regulating UHRF1 Expression.

Introduction Serine hydroxymethyltransferase 2 (SHMT2) has a critical role in serine-glycine metabolism to drive cancer cell proliferation. Yet, the function of SHMT2 in tumorigenesis, especially in human colorectal cancer (CRC) progression, remains largely unclear. Materials and Methods CRC and paired normal samples were collected in the Department of Colorectal Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, and assessed by real-time polymerase chain reaction (qPCR) analysis, western blot (WB), and immunohistochemistry (IHC). Moreover, SHMT2 expression in human CRC cells was identified by qPCR and WB. The CRC cell proliferation, migration, and invasion after SHMT2 knockdown were explored through in vitro and in vivo assays. mRNA-seq assays were used to investigate the underlying mechanisms behind the SHMT2 function. Results It was found that SHMT2 mRNA and protein were overexpressed in CRC tissue compared to the levels in normal mucosa. Positive expression of SHMT2 was significantly correlated with TNM stage and lymph node metastasis, and elevated expression of SHMT2 resulted as an independent prognostic factor in patients with CRC. SHMT2 knockdown impaired the proliferation of CRC in vitro and in vivo and induced cell cycle arrest by regulating UHRF1 expression. Conclusion Taken together, our findings reveal that UHRF1 is a novel target gene of SHMT2, which can be used as a potential therapeutic strategy for CRC therapy.

ARDS metabolic fingerprints: characterization, benchmarking, and potential mechanistic interpretation.

In this study, we aimed to identify acute respiratory distress syndrome (ARDS) metabolic fingerprints in selected patient cohorts and compare the metabolic profiles of direct versus indirect ARDS and hypoinflammatory versus hyperinflammatory ARDS. We hypothesized that the biological and inflammatory processes in ARDS would manifest as unique metabolomic fingerprints that set ARDS apart from other intensive care unit (ICU) conditions and could help examine ARDS subphenotypes and clinical subgroups. Patients with ARDS (n = 108) and ICU ventilated controls (n = 27) were included. Samples were randomly divided into 2/3 training and 1/3 test sets. Samples were analyzed using 1H nuclear magnetic resonance spectroscopy and gas chromatography-mass spectrometry. Twelve proteins/cytokines were also measured. Orthogonal partial least squares discriminant analysis (OPLS-DA) was used to select the most differentiating ARDS metabolites and protein/cytokines. Predictive performance of OPLS-DA models was measured in the test set. Temporal changes of metabolites were examined as patients progressed through ARDS until clinical recovery. Metabolic profiles of direct versus indirect ARDS subgroups and hypoinflammatory versus hyperinflammatory ARDS subgroups were compared. Serum metabolomics and proteins/cytokines had similar area under receiver operator curves when distinguishing ARDS from ICU controls. Pathway analysis of ARDS differentiating metabolites identified a dominant involvement of serine-glycine metabolism. In longitudinal tracking, the identified pathway metabolites generally exhibited correction by 7-14 days, coinciding with clinical improvement. ARDS subphenotypes and clinical subgroups were metabolically distinct. However, our identified metabolic fingerprints are not ARDS diagnostic biomarkers, and further research is required to ascertain generalizability. In conclusion, patients with ARDS are metabolically different from ICU controls. ARDS subphenotypes and clinical subgroups are metabolically distinct.

Cytoplasmic SHMT2 drives the progression and metastasis of colorectal cancer by inhibiting β-catenin degradation.

Introduction: Serine hydroxymethyltransferase 2 (SHMT2) plays a critical role in serine-glycine metabolism to drive cancer cell proliferation. However, the nonmetabolic function of SHMT2 in tumorigenesis, especially in human colorectal cancer (CRC) progression, remains largely unclear.Methods: SHMT2 expression in human CRC cells was identified by western blot and immunofluorescence assay. The CRC cell proliferation, migration, and invasion after SHMT2 knockdown or overexpression were explored through in vitro and in vivo assays. Immunofluorescence, mRNA-seq, co-immunoprecipitation, chromatin immunoprecipitation-qPCR and immunohistochemistry assays were used to investigate the underlying mechanisms behind the SHMT2 nonmetabolic function.Results: We demonstrated that SHMT2 was distributed in the cytoplasm and nucleus of human CRC cells. SHMT2 knockdown resulted in the significant inhibition of CRC cell proliferation, which was not restored by serine, glycine, or formate supplementation. The invasion and migration of CRC cells were suppressed after SHMT2 knockdown. Mechanistically, SHMT2 interacted with β-catenin in the cytoplasm. This interaction inhibited the ubiquitylation-mediated degradation of β-catenin and subsequently modulated the expression of its target genes, leading to the promotion of CRC cell proliferation and metastasis. Notably, the lysine 64 residue on SHMT2 (SHMT2K64) mediated its interaction with β-catenin. Moreover, transcription factor TCF4 interacted with β-catenin, which in turn increased SHMT2 expression, forming an SHMT2/β-catenin positive feedback loop. In vivo xenograft experiments confirmed that SHMT2 promoted the growth and metastasis of CRC cells. Finally, the level of SHMT2 was found to be significantly increased in human CRC tissues. The SHMT2 level was correlated with an increased level of β-catenin, associated with CRC progression and predicted poor patient survival.Conclusion: Taken together, our findings reveal a novel nonmetabolic function of SHMT2 in which it stabilizes β-catenin to prevent its ubiquitylation-mediated degradation and provide a potential therapeutic strategy for CRC therapy.

Modelling of SHMT1 riboregulation predicts dynamic changes of serine and glycine levels across cellular compartments

Human serine hydroxymethyltransferase (SHMT) regulates the serine-glycine one carbon metabolism and plays a role in cancer metabolic reprogramming. Two SHMT isozymes are acting in the cell: SHMT1 encoding the cytoplasmic isozyme, and SHMT2 encoding the mitochondrial one. Here we present a molecular model built on experimental data reporting the interaction between SHMT1 protein and SHMT2 mRNA, recently discovered in lung cancer cells. Using a stochastic dynamic model, we show that RNA moieties dynamically regulate serine and glycine concentration, shaping the system behaviour. For the first time we observe an active functional role of the RNA in the regulation of the serine-glycine metabolism and availability, which unravels a complex layer of regulation that cancer cells exploit to fine tune amino acids availability according to their metabolic needs. The quantitative model, complemented by an experimental validation in the lung adenocarcinoma cell line H1299, exploits RNA molecules as metabolic switches of the SHMT1 activity. Our results pave the way for the development of RNA-based molecules able to unbalance serine metabolism in cancer cells.

Unravelling Novel Insights into ARDS Pathophysiology

Characterization of key biological processes underpinning ARDS and the biological differences between disease subgroups (such as direct and indirect ARDS) can enhance our understanding of ARDS, its heterogeneity and may guide the development of specific therapies. In this study, we sought to explore mechanistic biological processes underlying ARDS using a metabolomics approach based on serum proton nuclear magnetic resonance spectroscopy (1H-NMR) and gas chromatography mass spectrometry (GC-MS) methodologies. Additionally, we sought to benchmark metabolomics ability for ARDS detection and subclassification against those of commonly published protein biomarkers and cytokines. Using 1H-NMR and GC-MS we characterized the metabolites that distinguish ARDS patients (n=68) from ICU ventilated controls (n=34). We further measured IL-6, IL-8, IL-10, TNF-a, Ang-2, RAGE, vWF, TNF-RI, ICAM-1, PAI-1, SP-D and Protein-C in ARDS patients and controls. Similarly, to explore ARDS heterogeneity, we identified metabolites and biomarkers that differentiate direct ARDS (n = 49) from indirect ARDS (n = 51). Pathway analysis was carried out to highlight the pathobiological processes underpinning ARDS development and heterogeneity. To characterize ARDS biomolecular processes, we prospectively tracked the metabolic changes in a cohort of ARDS patients (n = 44) as they progressed through ARDS until recovery. Our data indicates that metabolomics fared better than proteins/cytokines biomarkers, especially in differentiating direct and indirect ARDS. Pathway analysis of ARDS versus controls identified a dominant involvement of serine-glycine metabolism in a pattern suggestive of an encompassing theme of relative folate deficiency. In longitudinal tracking, folate-linked metabolites generally exhibit correction by 7-14 days, which parallels clinical improvements. Funding: This study was partly funded by a team grant from Alberta Innovates-Health Solutions (AIHS) to the Alberta Sepsis Network, Alberta’s Health Research Innovation Strategy grant to Brent W. Winston and Hans J. Vogel, Lung Association of Alberta grant to Brent W. Winston, a grant from the Canadian Intensive Care Foundation to Brent W. Winston, an Emerging Team Grant from Cumming School of Medicine, University of Calgary, Alberta Health Services awarded to Brent W. Winston and Hans J. Vogel. Declaration of Interest: None of the authors has any conflicts of interest or other financial disclosures to make. Ethical Approval: This study has been approved by the Calgary Health Research Ethics Board (REB15-0348).

Abstract 5471: EWS-FLI1 reprograms the metabolism of Ewing sarcoma cells via positive regulation of glutamine import and serine-glycine biosynthesis

Abstract Ewing sarcoma (EWS) is a soft tissue and bone tumor found primarily in adolescents and young adults. In most cases of EWS, the chimeric transcription factor, EWS-FLI1 is the primary oncogenic driver. The expression profile of EWS cells reflects EWS-FLI1 binding and activation or repression of transcription. Recent studies have shown EWS-FLI1 deregulates proteins that function in tryptophan metabolism (Mutz et al., 2016, FEBS Lett. 590, 2063) or serine-glycine biosynthesis (Tanner et al., 2017, Mol. Cancer Res., 11, 1517). In our study, we extend these findings by establishing that EWS-FLI1 transcriptionally regulates the expression of enzymes required for serine-glycine biosynthesis and the mitochondrial one-carbon cycle, and the uptake of the alternative nutrient source glutamine, directly. To identify metabolic pathways regulated by EWS-FLI1, we interrogated the expression profiles of EWS-FLI1-silenced TC32 EWS cells. We observed that silencing of EWS-FLI1 results in the decreased expression of genes required for serine-glycine biosynthesis specifically, PHGDH, PSAT1, PSPH, and SHMT2. Using ChIP analysis, we demonstrated that EWS-FLI1 binds specific regulatory regions within these four serine-glycine biosynthesis genes. Also, ectopic expression in 293T cells results in increased expression of PHGDH, PSAT1, PSPH, and SHMT2. Consistent with the ability of EWS cells to synthesize serine and glycine de novo, EWS cells grown in medium depleted of these amino acids exhibit no change in viability. However, EWS cells were sensitive to the depletion of glutamine. Analysis of the expression profiles of EWS-FLI1-silenced TC32 EWS cells showed EWS-FLI1 positively regulates expression of the glutamine transporter, SLC1A5 and that EWS cells require glutamine for glycine synthesis. Next, we examined metabolic processes downstream of serine-glycine biosynthesis and showed that enzymes associated with the mitochondrial one-carbon cycle, MTHFD2 and MTHD1L, are transcriptional targets of EWS-FLI1, but not their cytosolic counterpart MTHFD1. Our data suggests EWS-FLI1 favors activation of enzymes associated with the mitochondrial one-carbon cycle, which provides the reducing equivalents GSH and NADPH. Depletion of EWS-FLI1 or the inhibition of PHGDH reduced the GSH/GSSG and NADPH/NADP ratios in EWS cells resulting in increased production of reactive oxygen species, inducing DNA damage and apoptosis. Importantly, analysis of EWS primary tumor transcriptome data confirmed that the aforementioned metabolism genes we identified as regulated by EWS-FLI1 exhibit increased expression compared with normal tissues. In summary, our study demonstrates that EWS-FLI1 reprograms the metabolism of EWS cells and that serine-glycine metabolism and glutamine uptake are potential vulnerabilities in this tumor type. Citation Format: Nirmalya Sen, Allison M. Cross, Philip L. Lorenzi, Javed Khan, Berkley E. Gryder, Suntae Kim, Natasha J. Caplen. EWS-FLI1 reprograms the metabolism of Ewing sarcoma cells via positive regulation of glutamine import and serine-glycine biosynthesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5471.

Oxidized phospholipids regulate amino acid metabolism through MTHFD2 to facilitate nucleotide release in endothelial cells

Oxidized phospholipids (oxPAPC) induce endothelial dysfunction and atherosclerosis. Here we show that oxPAPC induce a gene network regulating serine-glycine metabolism with the mitochondrial methylenetetrahydrofolate dehydrogenase/cyclohydrolase (MTHFD2) as a causal regulator using integrative network modeling and Bayesian network analysis in human aortic endothelial cells. The cluster is activated in human plaque material and by atherogenic lipoproteins isolated from plasma of patients with coronary artery disease (CAD). Single nucleotide polymorphisms (SNPs) within the MTHFD2-controlled cluster associate with CAD. The MTHFD2-controlled cluster redirects metabolism to glycine synthesis to replenish purine nucleotides. Since endothelial cells secrete purines in response to oxPAPC, the MTHFD2-controlled response maintains endothelial ATP. Accordingly, MTHFD2-dependent glycine synthesis is a prerequisite for angiogenesis. Thus, we propose that endothelial cells undergo MTHFD2-mediated reprogramming toward serine-glycine and mitochondrial one-carbon metabolism to compensate for the loss of ATP in response to oxPAPC during atherosclerosis.

Serine-deficiency syndromes

Serine-deficiency disorders comprise a new group of neurometabolic diseases and are caused by defects in the biosynthesis of the amino acid L-serine. In contrast to most neurometabolic disorders, serine-deficiency disorders are potentially treatable. Furthermore, the severe neurological symptoms observed in patients underscore the important roles of the serine biosynthetic pathway in brain tissue. An overview of the patients with serine-deficiency disorders reported to date, the biochemical findings and the results of treatment with amino acids is presented. L-Serine biosynthesis plays an important role in multiple cellular reactions, particularly in the brain, as L-serine is a precursor of important metabolites such as nucleotides, phospholipids and the neurotransmitters glycine and D-serine. Disturbances of serine-glycine metabolism in relation to N-methyl-D-aspartate-receptor activation are supposed to play a role in psychiatric disease as well. Recent findings concerning these roles of L-serine-derived phospholipids and neurotransmitters are presented. Congenital microcephaly, seizures and severe psychomotor retardation are symptoms of serine deficiency and can be treated with supplementation of L-serine, sometimes combined with glycine. The symptoms observed in serine deficiency confirm that L-serine and L-serine-derived metabolites play important roles in the central nervous system.

Amino acid studies in transient acute polymorphic psychosis

Data are reviewed on the amino acid metabolism in patients suffering from transient acute polymorphic psychoses according to ICD-10. The psychotic episodes of many of these patients are characterized by distorted sensory perceptions and intense emotional states; plasma amino acid analysis revealed a disturbed serine-glycine metabolism.

Abnormal serine-glycine metabolism in the brains of schizophrenics

The metabolism of serine and glycine as studied in the plasma is abnormal in schizophrenics and psychotics. There is a concomitant abnormality of the enzyme serine hydroxymethyl transferase (SHMT). To study the status of serine-glycine metabolism in brains of schizophrenics and controls, frozen autopsied brain tissues were obtained from medial and lateral temporal lobes. The results show that the apparent K m of SHMT and the concentrations of serine and glycine are significantly higher only in the medial temporal lobe areas of schizophrenics when compared to controls. These findings are discussed in the context of the role of glycine and serine as enhancers of glutamatergic excitotoxicity and consequent development of morphological abnormalities in the brains of schizophrenics.

Serine and folate metabolism in fibroblasts from episodic psychotic patients with psychedelic symptoms

A disturbance of serine-glycine metabolism in a group of patients who became psychotic after oral intake of serine may be due to any serine-related enzyme abnormality. In order to elucidate this problem, we studied several enzymes in fibroblasts obtained from these patients. First, the enzyme serine hydroxymethyltransferase was investigated. The apparent K m values for serine, l-tetrahydrofolate (H 4folate), and pyridoxal 5′-phosphate, as well as the maximal velocities of the forward and backward reactions measured in fibroblasts obtained from patients, were not different from those in the cells from controls. We also measured the activities of another three enzymes of the folic acid cycle, viz., 5,10-methylene-H 4folate dehydrogenase, 10-formyl-H 4folate synthetase, and 5,10-methenyl-H 4 folate cyclohydrolase, as well as the enzyme cystathionine β-synthase. Again, no differences were found among these enzymes in fibroblasts from patients and controls. It can be concluded that the psychotic symptoms occurring after the administration of serine are not the result of any malfunctioning of the enzymes investigated.

Nutrition and Psychoses

Nutrition can be involved in the pathogenesis of psychotic disorders in a complex way. Nutrition deficiency syndromes in the matured adult brain are well studied, and have contribution considerably to the understanding of the biochemical bases of psychiatric illness. The importance of nutritional substances like the vitamins and trace elements in the development of psychotic disorders is stressed particularly by orthomolecular psychiatry. From the nutritional-metabolic point of view, a considerable number of hypotheses have arisen and discusses the findings concerning the metabolic and nutritional basis of schizo-affective psychoses. It can be concluded that a subtype of the schizo-affective disorders is caused by a disturbed serineglycine metabolism, which may result in the endogenous synthesis of hallucinogenic substances. This group of schizo-affective disorders can be distinguished from others by the presence of vivid perceptual anomalies. Dietary factors, such as catabolism, or an excess of serine and/or glycine contribute to the outbreak of this typical psychosis in susceptible persons, whereas a high carbohydrate, low protein, and low fat diet appears to be beneficial to these patients.

Research in biological psychiatry in the Netherlands; a brief survey

In this article a brief survey is given of the research in biological psychiatry in The Netherlands. The activities of the main research centres are focused on the pathogenesis of schizo-affective psychoses, especially the relation with the serine-glycine metabolism (Rotterdam), the psychopathological disorders characterized by mood and sleep disturbances, including the regulation of circadian processes (Groningen), and the significance of neuropeptides for psychopathological disorders e.g. schizophrenia, depression and cognitive disturbances (Utrecht).

Impaired glycine-serine conversion and increased plasma taurine levels in episodic psychotic patients with psychedelic symptoms

A disturbance of serine-glycine metabolism has been demonstrated in patients suffering from episodic acute psychosis, characterized by sensory perceptual distortions in whom oral loading with either serine or glycine induced psychedelic symptoms. Fasting plasma amino acid levels in oral serine-responsive patients were compared with those in glycine-responsive and manic-depressive patients. Only serine-responsive patients had a decreased plasma serine and increased plasma taurine concentration, while glycine responsive patients showed decreased alanine and manic-depressive patients an increased plasma glycine level. Amino acid analyses of plasma samples obtained after serine loading in patients and controls suggest that serine-responsive patients had an impaired conversion of glycine into serine. The results suggest that the higher plasma taurine level in serine-responsive patients is caused by an increased synthesis of taurine from homocysteine and serine. The limiting capacity of methyltetrahydrofolate-homocysteine methyltransferase coupled to increased formation of taurine may be responsible for the serine-evoked psychotic syndrome.

SCHIZOPHRENIA-LIKE PSYCHOSIS CAUSED BY A METABOLIC DISORDER

Four patients with an intermittent psychosis closely resembling hallucinogenic drug-induced states were suspected of having a porphyric disease and were investigated for a possible relation between the metabolic dysfunctions of porphyria and the psychotic syndrome. Theoretically the link could be in a disturbance of serine and glycine metabolism. This theory was supported by disturbances in serine and glycine excretion found in all patients during psychotic episodes. In addition, loading with one low oral dose of serine produced psychotic symptoms 5 h later which lasted 3-6 h. One patient reacted to glycine in the same way. These findings suggest that disturbed serine-glycine metabolism may have a key role in certain schizophreniform psychotic syndromes.

The relation of serine-glycine metabolism to the formation of single-carbon units

Cultivation of serine-glycine auxotrophs of Escherichia coli in a medium containing serine and a purine base results in a temporary inability of the cells to grow upon transfer to a medium containing glycine as the nutrilite. It could be shown that this failure to grow is due to the inability of the cells to obtain single-carbon units from glycine. The formation of the enzyme system required for the synthesis of single-carbon units from glycine seems to be controlled through repression exerted by the intracellular single carbons. The intracellular concentration of single-carbon units derived from the β-carbon of serine is apparently increased by the addition of a purine base to the growth medium.