scholarly journals The Role of the Mitochondrial Glycine Cleavage Complex in the Metabolism and Virulence of the Protozoan ParasiteLeishmania major

2007 ◽  
Vol 283 (1) ◽  
pp. 155-165 ◽  
Author(s):  
David A. Scott ◽  
Suzanne M. Hickerson ◽  
Tim J. Vickers ◽  
Stephen M. Beverley
Keyword(s):  
Cleavage Complex ◽  
Glycine Cleavage

scholarly journals Folate metabolic pathways in Leishmania

2011 ◽  
Vol 51 ◽  
pp. 63-80 ◽  
Author(s):  
Tim J. Vickers ◽  
Stephen M. Beverley
Keyword(s):  
Protective Immunity ◽  
Mitochondrial Protein ◽  
Purine Salvage ◽  
Genetic Studies ◽  
Ts Mutant ◽  
Metabolic Reactions ◽  
Cleavage Complex ◽  
Glycine Cleavage ◽  
Antifolate Drugs ◽  
Genus Leishmania

Trypanosomatid parasitic protozoans of the genus Leishmania are autotrophic for both folate and unconjugated pteridines. Leishmania salvage these metabolites from their mammalian hosts and insect vectors through multiple transporters. Within the parasite, folates are reduced by a bifunctional DHFR (dihydrofolate reductase)-TS (thymidylate synthase) and by a novel PTR1 (pteridine reductase 1), which reduces both folates and unconjugated pteridines. PTR1 can act as a metabolic bypass of DHFR inhibition, reducing the effectiveness of existing antifolate drugs. Leishmania possess a reduced set of folate-dependent metabolic reactions and can salvage many of the key products of folate metabolism from their hosts. For example, they lack purine synthesis, which normally requires 10-formyltetrahydrofolate, and instead rely on a network of purine salvage enzymes. Leishmania elaborate at least three pathways for the synthesis of the key metabolite 5,10-methylene-tetrahydrofolate, required for the synthesis of thymidylate, and for 10-formyltetrahydrofolate, whose presumptive function is for methionyl-tRNAMet formylation required for mitochondrial protein synthesis. Genetic studies have shown that the synthesis of methionine using 5-methyltetrahydrofolate is dispensable, as is the activity of the glycine cleavage complex, probably due to redundancy with serine hydroxymethyltransferase. Although not always essential, the loss of several folate metabolic enzymes results in attenuation or loss of virulence in animal models, and a null DHFR-TS mutant has been used to induce protective immunity. The folate metabolic pathway provides numerous opportunities for targeted chemotherapy, with strong potential for ‘repurposing' of compounds developed originally for treatment of human cancers or other infectious agents.

The 1986 Borden Award Lecture. The role of the kidney in amino acid metabolism and nutrition

1987 ◽  
Vol 65 (12) ◽  
pp. 2355-2362 ◽  
Author(s):  
John T. Brosnan
Keyword(s):  
Proximal Tubule ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Acid Metabolism ◽  
Rat Kidney ◽  
High Protein Diet ◽  
Serine Hydroxymethyltransferase ◽  
Glutamine Metabolism ◽  
Cleavage Enzyme ◽  
Glycine Cleavage

Measurement of the arteriovenous differences for free amino acids across rat kidney reveals that glycine and citrulline are removed and serine and arginine are added to the circulation. In addition, glutamine is taken up in large quantities by kidneys of animals that need to excrete large quantities of acid (e.g., diabetic animals, NH4Cl-fed animals, and animals fed a high protein diet). Glutamine is the major precursor of urinary ammonia and thus renal glutamine metabolism plays a key role in acid–base homeostasis. This process occurs primarily in the cells of the convoluted proximal tubule. Glutamine carbon is converted to glucose in acidotic rats and is totally oxidized in dogs. Regulation of glutamine metabolism occurs at two levels: acute regulation and chronic regulation. Acute regulation is, in part, mediated through a fall in intracellular [H+]. This activates α-ketoglutarate dehydrogenase and, ultimately, glutaminase. Chronic regulation involves induction of key enzymes, including, in the rat, glutaminase, glutamate dehydrogenase, and phosphoenolpyruvate carboxykinase. During the acidosis of prolonged starvation, the kidneys' requirement for glutamine must be met from muscle proteolysis and thus becomes a drain on lean body mass. Serine synthesis occurs by two separate pathways: from glycine by the combined actions of the glycine cleavage enzyme and serine hydroxymethyltransferase and from gluconeogenic precursors using the phosphorylated-intermediate pathway. Both pathways are located in the cells of the proximal tubule. Conversion of glycine to serine is ammoniagenic and the activity of the glycine cleavage enzyme is increased in acidosis. The function of serine synthesis by the phosphorylated-intermediate pathway is not apparent. Renal serine synthesis is quantitatively important; in man it is comparable to the serine obtained in the diet. Nevertheless, renal serine synthesis was not sensitive to serine status in rats as neither removal of dietary serine nor supplementation of the diet with serine affected renal serine synthesis. Arginine synthesis occurs from citrulline removed from the circulation. The citrulline is produced in the intestine. The kidney is the major endogenous source of arginine.

scholarly journals Phosphoserine Phosphatase Is Required for Serine and One-Carbon Unit Synthesis in Hydrogenobacter thermophilus

2017 ◽  
Vol 199 (21) ◽  
Author(s):  
Keugtae Kim ◽  
Yoko Chiba ◽  
Azusa Kobayashi ◽  
Hiroyuki Arai ◽  
Masaharu Ishii
Keyword(s):  
Physiological Role ◽  
Tca Cycle ◽  
Content Type ◽  
Phosphoserine Phosphatase ◽  
Genes Encoding ◽  
Hydrogenobacter Thermophilus ◽  
Glycine Cleavage ◽  
Major Donor ◽  
Serine Biosynthesis

ABSTRACT Hydrogenobacter thermophilus is an obligate chemolithoautotrophic bacterium of the phylum Aquificae and is capable of fixing carbon dioxide through the reductive tricarboxylic acid (TCA) cycle. The recent discovery of two novel-type phosphoserine phosphatases (PSPs) in H. thermophilus suggests the presence of a phosphorylated serine biosynthesis pathway; however, the physiological role of these novel-type metal-independent PSPs (iPSPs) in H. thermophilus has not been confirmed. In the present study, a mutant strain with a deletion of pspA, the catalytic subunit of iPSPs, was constructed and characterized. The generated mutant was a serine auxotroph, suggesting that the novel-type PSPs and phosphorylated serine synthesis pathway are essential for serine anabolism in H. thermophilus. As an autotrophic medium supplemented with glycine did not support the growth of the mutant, the reversible enzyme serine hydroxymethyltransferase does not appear to synthesize serine from glycine and may therefore generate glycine and 5,10-CH2-tetrahydrofolate (5,10-CH2-THF) from serine. This speculation is supported by the lack of glycine cleavage activity, which is needed to generate 5,10-CH2-THF, in H. thermophilus. Determining the mechanism of 5,10-CH2-THF synthesis is important for understanding the fundamental anabolic pathways of organisms, because 5,10-CH2-THF is a major one-carbon donor that is used for the synthesis of various essential compounds, including nucleic and amino acids. The findings from the present experiments using a pspA deletion mutant have confirmed the physiological role of iPSPs as serine producers and show that serine is a major donor of one-carbon units in H. thermophilus. IMPORTANCE Serine biosynthesis and catabolism pathways are intimately related to the metabolism of 5,10-CH2-THF, a one-carbon donor that is utilized for the biosynthesis of various essential compounds. For this reason, determining the mechanism of serine synthesis is important for understanding the fundamental anabolic pathways of microorganisms. In the present study, we experimentally confirmed that a novel phosphoserine phosphatase in the obligate chemolithoautotrophic bacterium Hydrogenobacter thermophilus is essential for serine biosynthesis. This finding indicates that serine is synthesized from an intermediate of gluconeogenesis in H. thermophilus. In addition, because glycine cleavage system activity and genes encoding an enzyme capable of producing 5,10-CH2-THF were not detected, serine appears to be the major one-carbon donor to tetrahydrofolate (THF) in H. thermophilus.

Suppression of food intake and growth by amino acids in Drosophila: the role of pumpless, a fat body expressed gene with homology to vertebrate glycine cleavage system

Development ◽  
1999 ◽  
Vol 126 (23) ◽  
pp. 5275-5284
Author(s):  
I. Zinke ◽  
C. Kirchner ◽  
L.C. Chao ◽  
M.T. Tetzlaff ◽  
M.J. Pankratz
Keyword(s):  
Amino Acids ◽  
Food Intake ◽  
Fat Body ◽  
Pupal Stage ◽  
Growth Defects ◽  
First Instar ◽  
Dependent Signal ◽  
Glycine Cleavage ◽  
Drosophila Mutant

We have isolated a Drosophila mutant, named pumpless, which is defective in food intake and growth at the larval stage. pumpless larvae can initially feed normally upon hatching. However, during late first instar stage, they fail to pump the food from the pharynx into the esophagus and concurrently begin moving away from the food source. Although pumpless larvae do not feed, they do not show the typical physiologic response of starving animals, such as upregulating genes involved in gluconeogenesis or lipid breakdown. The pumpless gene is expressed specifically in the fat body and encodes a protein with homology to a vertebrate enzyme involved in glycine catabolism. Feeding wild-type larvae high levels of amino acids could phenocopy the feeding and growth defects of pumpless mutants. Our data suggest the existence of an amino acid-dependent signal arising from the fat body that induces cessation of feeding in the larva. This signaling system may also mediate growth transition from larval to the pupal stage during Drosophila development.

Clinical effects of serine medication in non-ketotic hyperglycinaemia due to deficiency of p-protein of the glycine cleavage complex

1988 ◽  
Vol 11 (S2) ◽  
pp. 218-220 ◽  
Author(s):  
F. A. Wijburg ◽  
C. J. de Groot ◽  
R. B. H. Schutgens ◽  
P. G. Barth ◽  
K. Tada
Keyword(s):  
Clinical Effects ◽  
P Protein ◽  
Cleavage Complex ◽  
Glycine Cleavage

Strychnine Therapy in Nonketotic Hyperglycinemia

PEDIATRICS ◽  
1979 ◽  
Vol 63 (3) ◽  
pp. 369-373
Author(s):  
Dora Arneson ◽  
Lawrence T. Ch'ien ◽  
Philip Chance ◽  
R. Sidney Wilroy
Keyword(s):  
Sodium Benzoate ◽  
Inborn Error ◽  
Enzyme System ◽  
Inhibitory Neurotransmitter ◽  
Patient Reported ◽  
Cleavage Enzyme ◽  
Specific Antagonist ◽  
Glycine Cleavage ◽  
Nonketotic Hyperglycinemia

Nonketotic hyperglycinemia is an inborn error of metabolism resulting from a defect in the glycine cleavage enzyme system. It is characterized biochemically by elevated concentrations of glycine in blood, spinal fluid, and urine. Previous therapies which have been directed toward reducing the glycine concentration in plasma and CSF have not been successful in preventing neurological deterioration, which may be the result of the role of glycine as an inhibitory neurotransmitter. Strychnine treatment was initiated because it is a specific antagonist of glycine at postsynaptic membranes. The patient reported here has shown clinical and EEG improvement while taking strychnine in conjunction with sodium benzoate.

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