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The degradation of L-histidine in the rat. The formation of imidazolylpyruvate, imidazolyl-lactate and imidazolylpropionate.

ABSTRACT: 1. Soluble and mitochondrial forms of histidine-pyruvate aminotransferase were separated from rat liver preparations by chromatography on DEAE-cellulose. 2. These enzymes were characterized with respect to substrate specificity, substrate affinity, pH optimum, stability and molecular weight by chromatography on Sephadex G-200. 3. Each enzyme has a relatively broad specificity showing significant activity towards l-phenylalanine and l-tyrosine and catalysing transamination with a number of monocarboxylic 2-oxo acids. 2-Oxoglutarate is not a substrate for either enzyme. 4. The molecular weights of the two enzymes, by chromatography on Sephadex G-200, are in the range 130000-150000. 5. The formation in vitro of imidazolyl-lactate from imidazolylpyruvate and NADH was demonstrated by using liver preparations. 6. From a study of imidazolyl-lactate-NAD(+) oxidoreductase activity after electrophoresis of liver preparations on polyacrylamide gel, and from an examination of the activity of l-lactate-NAD(+) oxidoreductase (EC 1.1.1.27) towards imidazolylpyruvate, it is concluded that this latter enzyme is responsible for the formation of imidazolyl-lactate in the liver. 7. Preparations of bacteria obtained from rat faeces form imidazolylpropionate from l-histidine and urocanate without further subculture. The amount of imidazolylpropionate formed is increased under anaerobic conditions and more so in an atmosphere of H(2). It is suggested that the gut flora of the rat contribute largely, if not exclusively, to the formation of imidazolylpropionate normally found in the urine.

SUBMITTER: Emes AV

PROVIDER: S-EPMC1166000 | biostudies-other | 1973 Nov

REPOSITORIES: biostudies-other

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The degradation of L-histidine, imidazolyl-L-lactate and imidazolylpropionate by Pseudomonas testosteroni.

Project description:1. Imidazol-5-ylpropionate and imidazol-5-yl-lactate are degraded by Pseudomonas testosteroni via inducible pathways. 2. Growth on either compound as the sole source of carbon results in the induction of the enzymes for histidine catabolism. 3. The pathway of histidine degradation in this organism, a non-fluorescent Pseudomonad, is shown to be the same as that operating in Pseudomonas fluorescens and Pseudomonas putida. It consists of the successive formation of urocanate, imidazol-4-on-5-ylpropionate, N-formimino-l-glutamate, N-formyl-l-glutamate and glutamate. 4. Whole cells of P. testosteroni accumulate urocanate in the reaction mixture when incubated with imidazolylpropionate, but only after an adaptive lag period which is removed by previous growth on imidazolylpropionate as the source of carbon. 5. Imidazolyl-lactate is oxidized to imidazolylpyruvate, which then gives rise to histidine by specific transamination with l-glutamate. 6. Cells grown on histidine, urocanate or imidazolylpropionate are also able to degrade imidazolyllactate. 7. Mutants lacking urocanase are unable to grow on imidazolylpropionate, imidazolyl-lactate, histidine or urocanate. One with impaired histidase activity cannot utilize histidine or imidazolyl-lactate, but grows normally on imidazolylpropionate or urocanate. A mutant unable to grow on imidazolylpropionate is indistinguishable from the wild-type with respect to growth on histidine, imidazolyl-lactate or urocanate. 8. Thus it is established that imidazolyl-lactate is metabolized via histidine whereas imidazolylpropionate enters the histidine degradation pathway after conversion into urocanate.

| S-EPMC1177604 | biostudies-other

Effects of lactate on pathways of glycogen formation in the perfused rat liver.

Project description:In order to investigate the roles of lactate as substrate and regulator of hepatic glycogen synthesis, two groups of rat livers were perfused with oxygenated blood for 2 h. The initial perfusate glucose and lactate concentrations of Group I and II were 245 +/- 6.8 and 254 +/- 12.9 mg/dl and 49 +/- 2.6 and 54 +/- 2.2 mg/dl respectively. Labelled glucose was added to the perfusate to assess direct glycogen formation. Either additional glucose (Group I) or lactate (Group II) was added (1 mg/min) to a recirculating liver-perfusion system. Initial lactate uptake and glucose formation was identical in the two groups of studies. For Group I, both glucose and lactate uptake by the liver fell to nearly zero, in spite of increasing glucose concentrations. However, with lactate infusion (Group II), its uptake by the liver was maintained at 0.89 +/- 0.14 mg/min after 120 min. In total, 6.2 +/- 0.7 mg (Group I) or 20.2 +/- 3.9 mg (Group II) of glycogen was formed, 4.0 +/- 0.7 mg or 9.2 +/- 2.0 mg by direct synthesis from glucose and 2.2 +/- 0.3 mg or 11.0 +/- 2.1 mg by gluconeogenic formation, in Groups I and II respectively. With the provision of additional lactate, its uptake by the perfused liver tripled, as did glycogen synthesis. Glucose production doubled when lactate was added instead of glucose. Gluconeogenic formation of glycogen increased by 400%. Surprisingly, direct synthesis from glucose also rose by 130%. These data indicate that continued lactate uptake by the liver with gluconeogenic glycogen formation determines the amount of glycogen formed not only by this route, but also by direct synthesis from glucose.

| S-EPMC1130563 | biostudies-other

Saccharomyces cerevisiae Forms D-2-Hydroxyglutarate and Couples Its Degradation to D-Lactate Formation via a Cytosolic Transhydrogenase.

Project description:The D or L form of 2-hydroxyglutarate (2HG) accumulates in certain rare neurometabolic disorders, and high D-2-hydroxyglutarate (D-2HG) levels are also found in several types of cancer. Although 2HG has been detected in Saccharomyces cerevisiae, its metabolism in yeast has remained largely unexplored. Here, we show that S. cerevisiae actively forms the D enantiomer of 2HG. Accordingly, the S. cerevisiae genome encodes two homologs of the human D-2HG dehydrogenase: Dld2, which, as its human homolog, is a mitochondrial protein, and the cytosolic protein Dld3. Intriguingly, we found that a dld3? knock-out strain accumulates millimolar levels of D-2HG, whereas a dld2? knock-out strain displayed only very moderate increases in D-2HG. Recombinant Dld2 and Dld3, both currently annotated as D-lactate dehydrogenases, efficiently oxidized D-2HG to ?-ketoglutarate. Depletion of D-lactate levels in the dld3?, but not in the dld2? mutant, led to the discovery of a new type of enzymatic activity, carried by Dld3, to convert D-2HG to ?-ketoglutarate, namely an FAD-dependent transhydrogenase activity using pyruvate as a hydrogen acceptor. We also provide evidence that Ser3 and Ser33, which are primarily known for oxidizing 3-phosphoglycerate in the main serine biosynthesis pathway, in addition reduce ?-ketoglutarate to D-2HG using NADH and represent major intracellular sources of D-2HG in yeast. Based on our observations, we propose that D-2HG is mainly formed and degraded in the cytosol of S. cerevisiae cells in a process that couples D-2HG metabolism to the shuttling of reducing equivalents from cytosolic NADH to the mitochondrial respiratory chain via the D-lactate dehydrogenase Dld1.

| S-EPMC4813551 | biostudies-other

A bacterial basic region leucine zipper histidine kinase regulating toluene degradation.

Project description:The two-component signal transduction pathways in bacteria use a histidine-aspartate phosphorelay circuit to mediate cellular changes in response to environmental stimuli. Here we describe a novel two-component todST system, which activates expression of the toluene degradation (tod) pathway in Pseudomonas putida F1. The todS gene is predicted to encode a sensory hybrid kinase with two unique properties--a basic region leucine zipper dimerization motif at the N terminus and a duplicated histidine kinase motif. Evidence from a synthetic peptide model suggests that TodS binds as a dimer to a pseudopalindromic sequence (5'-TGACTCA), which resembles the recognition sequence of the eukaryotic transcription factors Fos and Jun. These results provide additional evidence that bacteria and eukaryotes share common regulatory motifs. The todT gene product, a response regulator, was overproduced as a fusion protein in Escherichia coli, and the purified protein was found to bind specifically to a 6-bp palindromic DNA structure in the tod control region. The phosphorylated form of TodT appears to be the activator of tod structural genes. This is the first report of a two-component system that regulates aromatic metabolism in bacteria.

| S-EPMC19812 | biostudies-literature

Amphiphilic Histidine-Based Oligopeptides Exhibit pH-Reversible Fibril Formation.

Project description:We report the design, simulation, synthesis, and reversible self-assembly of nanofibrils using polyhistidine-based oligopeptides. The inclusion of aromatic amino acids in the histidine block produces distinct antiparallel β-strands that lead to the formation of amyloid-like fibrils. The structures undergo self-assembly in response to a change in pH. This creates the potential to produce well-defined fibrils for biotechnological and biomedical applications that are pH-responsive in a physiologically relevant range.

| S-EPMC8375021 | biostudies-literature

The effects of glucose, acetate, lactate and insulin on protein degradation in the perfused rat heart.

Project description:Rat hearts were perfused as working preparations by the method of Taegtmeyer, Hems & Krebs [(1980 Biochem. J. 186, 701--711]. In the presence of glucose, insulin significantly inhibited protein degradation at concentrations as low as 50 mu units/ml. Acetate or lactate, when present either as sole fuel for contraction or in combination with glucose, did not inhibit protein degradation. Insulin inhibition or protein degradation was decreased with either lactate as sole fuel. We suggest that the inhibition of protein degradation occurs over the normal range of plasma concentrations of insulin present in vivo and that the presence of glucose may be at least in part necessary for this effect of insulin.

| S-EPMC1158612 | biostudies-other

Ionic properties of an essential histidine residue in pig heart lactate dehydrogenase.

Project description:1. Pig heart lactate dehydrogenase is inhibited by addition of one equivalent of diethyl pyrocarbonate. The inhibition is due to the acylation of a unique histidine residue which is 10-fold more reactive than free histidine. No other amino acid side chains are modified. 2. The carbethoxyhistidine residue slowly decomposes and the enzyme activity reappears. 3. The essential histidine residue is only slightly protected by the presence of NADH but is completely protected when substrate and substrate analogues bind to the enzyme-NADH complex. The protection is interpreted in terms of a model in which substrates can only bind to the enzyme in which the histidine residue is protonated and is thus not available for reaction with the acylating agent. 4. The apparent pK(a) of the histidine residue in the apoenzyme is 6.8+/-0.2. In the enzyme-NADH complex it is 6.7+/-0.2. 5. Acylated enzyme binds NADH with unchanged affinity. The enzyme is inhibited because substrates and substrate analogues cannot bind at the acylated histidine residue in the enzyme-NADH complex.

| S-EPMC1177532 | biostudies-other

Lactate regulates rat male germ cell function through reactive oxygen species.

Project description:Besides giving structural support, Sertoli cells regulate the fate of germ cells by supplying a variety of factors. These factors include hormones, several pro- and anti-apoptotic agents and also energetic substrates. Lactate is one of the compounds produced by Sertoli cells, which is utilized as an energetic substrate by germ cells, particularly spermatocytes and spermatids. Beyond its function as an energy source, some studies have proposed a role of lactate in the regulation of gene expression not strictly related to the energetic state of the cells. The general hypothesis that motivated this investigation was that lactate affects male germ cell function, far beyond its well-known role as energetic substrate. To evaluate this hypothesis we investigated: 1) if lactate was able to regulate germ cell gene expression and if reactive oxygen species (ROS) participated in this regulation, 2) if different signal transduction pathways were modified by the production of ROS in response to lactate and 3) possible mechanisms that may be involved in lactate stimulation of ROS production. In order to achieve these goals, cultures of germ cells obtained from male 30-day old rats were exposed to 10 or 20 mM lactate. Increases in lactate dehydrogenase (LDH) C and monocarboxylate transporter (MCT)2 expression, in Akt and p38-MAPK phosphorylation levels and in ROS production were observed. These effects were impaired in the presence of a ROS scavenger. Lactate stimulated ROS production was also inhibited by a LDH inhibitor or a NAD(P)H oxidase (NOX) inhibitor. NOX4 expression was identified in male germ cells. The results obtained herein are consistent with a scenario where lactate, taken up by germ cells, becomes oxidized to pyruvate with the resultant increase in NADH, which is a substrate for NOX4. ROS, products of NOX4 activity, may act as second messengers regulating signal transduction pathways and gene expression.

| S-EPMC3909278 | biostudies-literature

Lactate mediated epigenetic reprogramming during cancer associated fibroblast formation

Project description:We report oxidative bisulfite analysis of whole genome methylation of mesenchymal stem cells (MSCs) and Cancer associated fibroblasts (CAFs)

2019-12-04 | GSE135218 | GEO

Histidine degradation via an aminotransferase increases the nutritional flexibility of Candida glabrata.

Project description:The ability to acquire nutrients during infections is an important attribute in microbial pathogenesis. Amino acids are a valuable source of nitrogen if they can be degraded by the infecting organism. In this work, we analyzed histidine utilization in the fungal pathogen of humans Candida glabrata. Hemiascomycete fungi, like C. glabrata or Saccharomyces cerevisiae, possess no gene coding for a histidine ammonia-lyase, which catalyzes the first step of a major histidine degradation pathway in most other organisms. We show that C. glabrata instead initializes histidine degradation via the aromatic amino acid aminotransferase Aro8. Although ARO8 is also present in S. cerevisiae and is induced by extracellular histidine, the yeast cannot use histidine as its sole nitrogen source, possibly due to growth inhibition by a downstream degradation product. Furthermore, C. glabrata relies only on Aro8 for phenylalanine and tryptophan utilization, since ARO8, but not its homologue ARO9, was transcriptionally activated in the presence of these amino acids. Accordingly, an ARO9 deletion had no effect on growth with aromatic amino acids. In contrast, in S. cerevisiae, ARO9 is strongly induced by tryptophan and is known to support growth on aromatic amino acids. Differences in the genomic structure of the ARO9 gene between C. glabrata and S. cerevisiae indicate a possible disruption in the regulatory upstream region. Thus, we show that, in contrast to S. cerevisiae, C. glabrata has adapted to use histidine as a sole source of nitrogen and that the aromatic amino acid aminotransferase Aro8, but not Aro9, is the enzyme required for this process.

| S-EPMC4054274 | biostudies-literature

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