Dihydropteroate synthase

Dihydropteroate synthase type-1
	according to PDB 1AJ0
other names	Dihydropteroate pyrophosphorylase type I, Dihydropteroate synthase type I, DHPS
Mass / length primary structure	30,126 Da / 279 amino acids
Secondary to quaternary structure	Homodimer or homotrimer
Identifier
External IDs	UniProt : P0C002 ;
Enzyme classification
EC, category	2.5.1.15
Substrate	(7,8-dihydropterin-6-yl) methyl diphosphate + 4-aminobenzoate
Products	7,8-dihydropteroate + PP i
	Orthologue

The dihydropteroate synthase (DHPS) is an enzyme that in the folic acid -Metabolism of bacteria , fungi and plants occurs, but not in animals. In archaea , dihydropteroate synthase is involved in the biosynthesis of methanopterin . Folic acid is not produced in animals and is a vitamin that must be obtained through food.

properties

The dihydropteroate synthase catalyzes the following reaction:

(7,8-dihydropterin-6-yl) methyl diphosphate + 4-aminobenzoate (PABA) 7,8-dihydropteroate (H2Pte) + diphosphate ${\ displaystyle \ rightleftharpoons}$

Dihydropteroate synthase ( DHPS ) reaction mechanism . (1) : (7,8-dihydropterin-6-yl) methyl diphosphate; (2) : 4-aminobenzoate; (3) : 7,8-dihydropteroate; (4) : diphosphate

The sulfonamides , a class of antibiotics , are competitive inhibitors of the binding of 4-aminobenzoate to dihydropteroate synthase. However, various pathogens have developed resistance mechanisms to inhibition by sulfonamides, including through point mutations in the dihydropteroate synthase, such as Plasmodium falciparum against sulfadoxine - pyrimethamine or Pneumocystis jirovecii against trimethoprim and sulfamethoxazole . In Escherichia coli , the gene for dihydropteroate synthase (gene sulI ) is located on various resistance plasmids and on Tn21- related transposons . The plasmid pDGO100 contains two copies of sulI .

In plants such as Arabidopsis thaliana , dihydropteroate synthase is part of a mitochondrial enzyme complex made up of two enzymes with 2-amino-4-hydroxy-6-hydroxymethyldihydropteridine diphosphokinase , as is the case in the fungus Pneumocystis jirovecii (gene fas ). In the yeast Saccharomyces cerevisiae , this enzyme complex (dihydropteroate synthase gene fol1 ) has a third enzyme, dihydroneopterin aldolase .

literature

C. Capasso, CT Supuran: Sulfa and trimethoprim-like drugs - antimetabolites acting as carbonic anhydrase, dihydropteroate synthase and dihydrofolate reductase inhibitors. In: Journal of enzyme inhibition and medicinal chemistry. Volume 29, Number 3, June 2014, pp. 379-387, doi : 10.3109 / 14756366.2013.787422 , PMID 23627736 .

Web links

MeSH dihydropteroate synthase

Individual evidence

↑ ^a ^b EC 2.5.1.15. In: sbcs.qmul.ac.uk. Retrieved July 9, 2018 .
↑ MK Yun, Y. Wu, Z. Li, Y. Zhao, MB Waddell, AM Ferreira, RE Lee, D. Bashford, SW White: Catalysis and sulfa drug resistance in dihydropteroate synthase. In: Science . Volume 335, number 6072, March 2012, pp. 1110–1114, doi : 10.1126 / science.1214641 , PMID 22383850 , PMC 3531234 (free full text).
^ A. Heinberg, L. Kirkman: The molecular basis of antifolate resistance in Plasmodium falciparum: looking beyond point mutations. In: Annals of the New York Academy of Sciences. Volume 1342, April 2015, pp. 10-18, doi : 10.1111 / nyas.12662 , PMID 25694157 , PMC 4405445 (free full text) (review).
↑ YS Huang, JJ Yang, NY Lee, GJ Chen, WC Ko, HY Sun, CC Hung: Treatment of Pneumocystis jirovecii pneumonia in HIV-infected patients: a review. In: Expert review of anti-infective therapy. Volume 15, number 9, 09 2017, pp. 873-892, doi : 10.1080 / 14787210.2017.1364991 , PMID 28782390 .
↑ ^a ^b sulI - Dihydropteroate synthase type-1 - Escherichia coli - sulI gene & protein. In: uniprot.org. June 20, 2018, accessed July 9, 2018 .
↑ S. Storozhenko, O. Navarrete, S. Ravanel, V. De Brouwer, P. Chaerle, GF Zhang, O. Bastien, W. Lambert, F. Rébeillé, D. Van Der Straeten: Cytosolic hydroxymethyldihydropterin pyrophosphokinase / dihydropteroate synthase from Arabidopsis thaliana: a specific role in early development and stress response. In: Journal of Biological Chemistry . Volume 282, Number 14, April 2007, pp. 10749-10761, doi : 10.1074 / jbc.M701158200 , PMID 17289662 .
↑ F. Volpe, M. Dyer, JG Scaife, G. Darby, DK Stammers, CJ Delves: The multifunctional folic acid synthesis fas gene of Pneumocystis carinii appears to encode dihydropteroate synthase and hydroxymethyldihydropterin pyrophosphokinase. In: Genes. Volume 112, Number 2, March 1992, pp. 213-218, PMID 1313386 .
↑ U. Güldener, GJ Koehler, C. Haussmann, A. Bacher, J. Kricke, D. Becher, JH Hegemann: Characterization of the Saccharomyces cerevisiae Fol1 protein: starvation for C1 carrier induces pseudohyphal growth. In: Molecular biology of the cell. Volume 15, number 8, August 2004, pp. 3811-3828, doi : 10.1091 / mbc.e03-09-0680 , PMID 15169867 , PMC 491839 (free full text).

[ac-25115-1] EC 2.5.1.15. In: sbcs.qmul.ac.uk. Retrieved July 9, 2018 .

[2] MK Yun, Y. Wu, Z. Li, Y. Zhao, MB Waddell, AM Ferreira, RE Lee, D. Bashford, SW White: Catalysis and sulfa drug resistance in dihydropteroate synthase. In: Science . Volume 335, number 6072, March 2012, pp. 1110–1114, doi : 10.1126 / science.1214641 , PMID 22383850 , PMC 3531234 (free full text).

[3] A. Heinberg, L. Kirkman: The molecular basis of antifolate resistance in Plasmodium falciparum: looking beyond point mutations. In: Annals of the New York Academy of Sciences. Volume 1342, April 2015, pp. 10-18, doi : 10.1111 / nyas.12662 , PMID 25694157 , PMC 4405445 (free full text) (review).

[4] YS Huang, JJ Yang, NY Lee, GJ Chen, WC Ko, HY Sun, CC Hung: Treatment of Pneumocystis jirovecii pneumonia in HIV-infected patients: a review. In: Expert review of anti-infective therapy. Volume 15, number 9, 09 2017, pp. 873-892, doi : 10.1080 / 14787210.2017.1364991 , PMID 28782390 .

[uniprot-0002-5] sulI - Dihydropteroate synthase type-1 - Escherichia coli - sulI gene & protein. In: uniprot.org. June 20, 2018, accessed July 9, 2018 .

[6] S. Storozhenko, O. Navarrete, S. Ravanel, V. De Brouwer, P. Chaerle, GF Zhang, O. Bastien, W. Lambert, F. Rébeillé, D. Van Der Straeten: Cytosolic hydroxymethyldihydropterin pyrophosphokinase / dihydropteroate synthase from Arabidopsis thaliana: a specific role in early development and stress response. In: Journal of Biological Chemistry . Volume 282, Number 14, April 2007, pp. 10749-10761, doi : 10.1074 / jbc.M701158200 , PMID 17289662 .

[7] F. Volpe, M. Dyer, JG Scaife, G. Darby, DK Stammers, CJ Delves: The multifunctional folic acid synthesis fas gene of Pneumocystis carinii appears to encode dihydropteroate synthase and hydroxymethyldihydropterin pyrophosphokinase. In: Genes. Volume 112, Number 2, March 1992, pp. 213-218, PMID 1313386 .

[8] U. Güldener, GJ Koehler, C. Haussmann, A. Bacher, J. Kricke, D. Becher, JH Hegemann: Characterization of the Saccharomyces cerevisiae Fol1 protein: starvation for C1 carrier induces pseudohyphal growth. In: Molecular biology of the cell. Volume 15, number 8, August 2004, pp. 3811-3828, doi : 10.1091 / mbc.e03-09-0680 , PMID 15169867 , PMC 491839 (free full text).