Wikipedia preview

出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2014/09/02 20:49:07」(JST)

wiki en

Dihydropteroate synthase is an enzyme classified under EC 2.5.1.15. It produces dihydropteroate in bacteria, but it is not expressed in most eukaryotes including humans. This makes it a useful target for sulfonamide antibiotics, which compete with the PABA precursor.

(2-amino-4-hydroxy-7,8-dihydropteridin-6-yl)methyl diphosphate + 4-aminobenzoate (PABA) diphosphate + dihydropteroate.

All organisms require reduced folate cofactors for the synthesis of a variety of metabolites. Most microorganisms must synthesize folate de novo because they lack the active transport system of higher vertebrate cells that allows these organisms to use dietary folates. Proteins containing this domain include dihydropteroate synthase (EC 2.5.1.15) as well as a group of methyltransferase enzymes including methyltetrahydrofolate, corrinoid iron-sulphur protein methyltransferase (MeTr) Q46389 that catalyses a key step in the Wood-Ljungdahl pathway of carbon dioxide fixation.

Dihydropteroate synthase (EC 2.5.1.15) (DHPS) catalyses the condensation of 6-hydroxymethyl-7,8-dihydropteridine pyrophosphate to para-aminobenzoic acid to form 7,8-dihydropteroate. This is the second step in the three-step pathway leading from 6-hydroxymethyl-7,8-dihydropterin to 7,8-dihydrofolate. DHPS is the target of sulphonamides, which are substrate analogues that compete with para-aminobenzoic acid. Bacterial DHPS (gene sul or folP)^[1] is a protein of about 275 to 315 amino acid residues that is either chromosomally encoded or found on various antibiotic resistance plasmids. In the lower eukaryote Pneumocystis carinii, DHPS is the C-terminal domain of a multifunctional folate synthesis enzyme (gene fas).^[2]

References

^ Crawford IP, Slock J, Stahly DP, Six EW, Han CY (1990). "An apparent Bacillus subtilis folic acid biosynthetic operon containing pab, an amphibolic trpG gene, a third gene required for synthesis of para-aminobenzoic acid, and the dihydropteroate synthase gene". J. Bacteriol. 172 (12): 7211–7226. PMC 210846. PMID 2123867.
^ Volpe F, Dyer M, Scaife JG, Darby G, Stammers DK, Delves CJ (1992). "The multifunctional folic acid synthesis fas gene of Pneumocystis carinii appears to encode dihydropteroate synthase and hydroxymethyldihydropterin pyrophosphokinase". Gene 112 (2): 213–218. doi:10.1016/0378-1119(92)90378-3. PMID 1313386.

External links

Dihydropteroate synthetase at the US National Library of Medicine Medical Subject Headings (MeSH)

This article incorporates text from the public domain Pfam and InterPro IPR000489

This enzyme-related article is a stub. You can help Wikipedia by expanding it.

UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

1. ヘキソースリン酸側路およびグルタチオン代謝関連疾患 related disorders of the hexose monophosphate shunt and glutathione metabolism
2. トリメトプリムスルファメトキサゾール：概要 trimethoprim sulfamethoxazole an overview
3. HIV感染患者におけるニューモシスチス感染の予防 prophylaxis against pneumocystis infection in hiv infected patients
4. 尿素サイクル障害：管理 urea cycle disorders management
5. 尿素サイクル障害：臨床的特徴および診断 urea cycle disorders clinical features and diagnosis

English Journal

Multilocus Microsatellite Genotyping Array for Investigation of Genetic Epidemiology of Pneumocystis jirovecii.

Parobek CM1, Jiang LY, Patel JC, Alvarez-Martínez MJ, Miro JM, Worodria W, Andama A, Fong S, Huang L, Meshnick SR, Taylor SM, Juliano JJ.Author information 1School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.AbstractPneumocystis jirovecii is a symbiotic respiratory fungus that causes pneumonia (PcP) in immunosuppressed patients. Because P. jirovecii cannot be reliably cultured in vitro, it has proven difficult to study and gaps in our understanding of the organism persist. The release of a draft genome for the organism opens the door for the development of new genotyping approaches for studying its molecular epidemiology and global population structure. We identified and validated 8 putatively neutral microsatellite markers and 1 microsatellite marker linked to the dihydropteroate synthase gene (dhps), the enzymatic target of sulfa drugs used for PcP prevention and treatment. Using these tools, we analyzed P. jirovecii isolates from HIV-infected patients from three geographically distant populations: Uganda, the United States, and Spain. Among the 8 neutral markers, we observed high levels of allelic heterozygosity (average He, 0.586 to 0.842). Consistent with past reports, we observed limited global population structuring, with only the Ugandan isolates showing minor differentiation from the other two populations. In Ugandan isolates that harbored mutations in dhps, the microsatellite locus linked to dhps demonstrated a depressed He, consistent with positive directional selection for sulfa resistance mutations. Using a subset of these microsatellites, analyses of individual and paired samples from infections in San Francisco, CA, showed reliable typeability within a single infection and high discriminatory power between infections. These features suggest that this novel microsatellite typing approach will be an effective tool for molecular-epidemiological investigations into P. jirovecii population structure, transmission, and drug resistance.
Journal of clinical microbiology.J Clin Microbiol.2014 May;52(5):1391-9. doi: 10.1128/JCM.02531-13. Epub 2014 Feb 12.
Pneumocystis jirovecii is a symbiotic respiratory fungus that causes pneumonia (PcP) in immunosuppressed patients. Because P. jirovecii cannot be reliably cultured in vitro, it has proven difficult to study and gaps in our understanding of the organism persist. The release of a draft genome for the
PMID 24523468

Identification and Characterization of an Allosteric Inhibitory Site on Dihydropteroate Synthase.

Hammoudeh DI1, Daté M, Yun MK, Zhang W, Boyd VA, Viacava Follis A, Griffith E, Lee RE, Bashford D, White SW.Author information 1Departments of †Structural Biology and ‡Chemical Biology and Therapeutics, St. Jude Children's Research Hospital , Memphis, Tennessee 38105, United States.AbstractThe declining effectiveness of current antibiotics due to the emergence of resistant bacterial strains dictates a pressing need for novel classes of antimicrobial therapies, preferably against molecular sites other than those in which resistance mutations have developed. Dihydropteroate synthase (DHPS) catalyzes a crucial step in the bacterial pathway of folic acid synthesis, a pathway that is absent in higher vertebrates. As the target of the sulfonamide class of drugs that were highly effective until resistance mutations arose, DHPS is known to be a valuable bacterial Achilles heel that is being further exploited for antibiotic development. Here, we report the discovery of the first known allosteric inhibitor of DHPS. NMR and crystallographic studies reveal that it engages a previously unknown binding site at the dimer interface. Kinetic data show that this inhibitor does not prevent substrate binding but rather exerts its effect at a later step in the catalytic cycle. Molecular dynamics simulations and quasi-harmonic analyses suggest that the effect of inhibitor binding is transmitted from the dimer interface to the active-site loops that are known to assume an obligatory ordered substructure during catalysis. Together with the kinetics results, these structural and dynamics data suggest an inhibitory mechanism in which binding at the dimer interface impacts loop movements that are required for product release. Our results potentially provide a novel target site for the development of new antibiotics.
ACS chemical biology.ACS Chem Biol.2014 Mar 27. [Epub ahead of print]
The declining effectiveness of current antibiotics due to the emergence of resistant bacterial strains dictates a pressing need for novel classes of antimicrobial therapies, preferably against molecular sites other than those in which resistance mutations have developed. Dihydropteroate synthase (DH
PMID 24650357

Japanese Journal

Longitudinal survey of Plasmodium falciparum infection in Vietnam: characteristics of antimalarial resistance and their associated factors.

Isozumi Rie,Uemura Haruki,Le Duc Dao,Truong Van Hanh,Nguyen Duc Giang,Ha Viet Vien,Bui Quang Phuc,Nguyen Van Tuan,Nakazawa Shusuke
Journal of clinical microbiology 48(1), 70-77, 2010-01
… falciparum dihydropteroate synthetase (PfDHPS) was observed in 2002. …
NAID 120002153040

グラム陰性菌における非伝達性サルファ剤耐性プラスミッドの遺伝的解析

加藤益弘,井上松久
北関東医学 33(1), 77-83, 1983
… pSu, except one, is mostly due to the formation of Su-resistant dihydropteroate synthetase (DHPS). …
NAID 130003452696

Plasmid-Mediated Sulfanilamide Resistance

, , ,
MICROBIOLOGY and IMMUNOLOGY 22(7), 367-375, 1978
… Dihydropteroate synthetase (DHPS) is specified by a substrain of <I>Escherichia coli</I> …
NAID 130003482723

Related Pictures

★リンクテーブル★

リンク元	「プテリジン」
関連記事	「synthetase」「dihydropteroate」

「プテリジン」

Pterin binding enzyme
Identifiers
Symbol	Pterin_bind
Pfam	PF00809
InterPro	IPR000489
PROSITE	PDOC00630
SCOP	1ajz
SUPERFAMILY	1ajz
Available protein structures:
Pfam	structures
PDB	RCSB PDB; PDBe; PDBj
PDBsum	structure summary

Search
PMC	articles
PubMed	articles
NCBI	proteins

Dihydropteroate synthase
	Tetrahydrofolate synthesis pathway
Identifiers
EC number	2.5.1.15
CAS number	9055-61-2
Databases
IntEnz	IntEnz view
BRENDA	BRENDA entry
ExPASy	NiceZyme view
KEGG	KEGG entry
MetaCyc	metabolic pathway
PRIAM	profile
PDB structures	RCSB PDB PDBe PDBsum
Gene Ontology	AmiGO / EGO
Search
PMC	articles
PubMed	articles
NCBI	proteins