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.

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

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

FAMILIAL ASPECTS OF OBESITY

PEDIATRICS ◽  
1957 ◽  
Vol 20 (3) ◽  
pp. 547-549
Author(s):  
Barton Childs
Keyword(s):  
Gene Action ◽  
Human Populations ◽  
Heritable Variation ◽  
Genetic Studies ◽  
Actual Measurement ◽  
Wide Range ◽  
Discontinuous Variation ◽  
Number Of Genes ◽  
Molecular Specificity ◽  
Metabolic Reactions

NO SCIENTIFIC investigation is needed to detect the familial nature of obesity, but the extent of the contribution of constitutional, cultural and other environmental components is not at all clear. That it is especially important, however, to understand these etiologic factors is suggested by the failures experienced by those who have undertaken to treat long standing obesity. A firm grasp of the nature of the causes of the condition is the key to prevention, and the time to prevent is childhood. Before going on to a discussion of heredity in obesity it might be well to state what is possible in genetic studies on human populations. Genetics is the study of heritable variation, and it attempts to describe the degree to which familial like-nesses and dissimilarities result from the action of genes in particular environments. In general, we suppose that gene action is biochemical, and that it is expressed in the control of metabolic reactions in the cells, whether by conferring specificity upon enzymes or by other means. Several methods for such investigation are available. First we may study discontinuous variation in which differences between individuals are clearly measureable, and a population may be divided into two or several types without misclassification. Such differences are often found to be associated with differences in molecular specificity or quantitative differences in enzyme activity. If these differences are genetic in origin, they are usually found to be due to one or at most a small number of genes, and the intrafamily distribution of the characteristics will follow some mendelian pattern. A second method involves the analysis of continuous variation. By this is meant differences between individuals which are so small as to make actual measurement of such differences impossible, and covering a wide range or spectrum, so as to form a continuum.

scholarly journals Assembly of the [4Fe–4S] cluster of NFU1 requires the coordinated donation of two [2Fe–2S] clusters from the scaffold proteins, ISCU2 and ISCA1

2020 ◽  
Vol 29 (19) ◽  
pp. 3165-3182 ◽  
Author(s):  
Anshika Jain ◽  
Anamika Singh ◽  
Nunziata Maio ◽  
Tracey A Rouault
Keyword(s):  
Pyruvate Dehydrogenase ◽  
Alpha Helix ◽  
Scaffold Proteins ◽  
Mitochondrial Dysfunctions ◽  
Iron Sulfur ◽  
Key Enzyme ◽  
Cleavage Complex ◽  
Glycine Cleavage ◽  
Alpha Ketoglutarate Dehydrogenase ◽  
Enzyme Complexes

Abstract NFU1, a late-acting iron–sulfur (Fe–S) cluster carrier protein, has a key role in the pathogenesis of the disease, multiple mitochondrial dysfunctions syndrome. In this work, using genetic and biochemical approaches, we identified the initial scaffold protein, mitochondrial ISCU (ISCU2) and the secondary carrier, ISCA1, as the direct donors of Fe–S clusters to mitochondrial NFU1, which appears to dimerize and reductively mediate the formation of a bridging [4Fe–4S] cluster, aided by ferredoxin 2. By monitoring the abundance of target proteins that acquire their Fe–S clusters from NFU1, we characterized the effects of several novel pathogenic NFU1 mutations. We observed that NFU1 directly interacts with each of the Fe–S cluster scaffold proteins known to ligate [2Fe–2S] clusters, ISCU2 and ISCA1, and we mapped the site of interaction to a conserved hydrophobic patch of residues situated at the end of the C-terminal alpha-helix of NFU1. Furthermore, we showed that NFU1 lost its ability to acquire its Fe–S cluster when mutagenized at the identified site of interaction with ISCU2 and ISCA1, which thereby adversely affected biochemical functions of proteins that are thought to acquire their Fe–S clusters directly from NFU1, such as lipoic acid synthase, which supports the Fe–S-dependent process of lipoylation of components of multiple key enzyme complexes, including pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase and the glycine cleavage complex.

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