Dihydropteroate synthase

Last updated
Dihydropteroate synthetase
THFsynthesispathway.png
Tetrahydrofolate synthesis pathway
Identifiers
EC no. 2.5.1.15
CAS no. 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 / QuickGO
Search
PMC articles
PubMed articles
NCBI proteins
Pterin binding enzyme
Identifiers
SymbolPterin_bind
Pfam PF00809
InterPro IPR000489
PROSITE PDOC00630
SCOP2 1ajz / SCOPe / SUPFAM
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary
PDB 1twz A:28-230 1tws A:28-230 1tww B:28-230

1tx0 A:28-230 1tx2 A:28-230 1ad1 B:9-210 1ad4 A:9-210 1eye A:11-220 1ajz :20-228 1aj2 :20-228 1aj0 :20-228 2bmb A:509-774 1q8a B:315-515 1q7z B:315-515 1q85 A:315-515 1q8j A:315-515 1q7q B:315-515 1q7m A:315-515

1f6y A:1-206

Dihydropteroate synthase (DHPS) 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.

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) [1] 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 sulfonamides, which are substrate analogues that compete with para-aminobenzoic acid. Bacterial DHPS (gene sul or folP) [2] 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 fungus Pneumocystis jirovecii (previously P. carinii) DHPS is the C-terminal domain of a multifunctional folate synthesis enzyme (gene fas). [3]

Related Research Articles

4-Aminobenzoic acid (also known as para-aminobenzoic acid or PABA because the two functional groups are attached to the benzene ring across from one another in the para position) is an organic compound with the formula H2NC6H4CO2H. PABA is a white solid, although commercial samples can appear gray. It is slightly soluble in water. It consists of a benzene ring substituted with amino and carboxyl groups. The compound occurs extensively in the natural world.

<span class="mw-page-title-main">Folinic acid</span> Derivative of folic acid used in cancer treatment

Folinic acid, also known as leucovorin, is a medication used to decrease the toxic effects of methotrexate and pyrimethamine. It is also used in combination with 5-fluorouracil to treat colorectal cancer and pancreatic cancer, may be used to treat folate deficiency that results in anemia, and methanol poisoning. It is taken by mouth, injection into a muscle, or injection into a vein.

<span class="mw-page-title-main">Sulfamethoxazole</span> Chemical compound

Sulfamethoxazole is an antibiotic. It is used for bacterial infections such as urinary tract infections, bronchitis, and prostatitis and is effective against both gram negative and positive bacteria such as Escherichia coli and Listeria monocytogenes.

<span class="mw-page-title-main">Pterin</span> Chemical compound

Pterin is a heterocyclic compound composed of a pteridine ring system, with a "keto group" and an amino group on positions 4 and 2 respectively. It is structurally related to the parent bicyclic heterocycle called pteridine. Pterins, as a group, are compounds related to pterin with additional substituents. Pterin itself is of no biological significance.

<span class="mw-page-title-main">Pyrimethamine</span> Medication

Pyrimethamine, sold under the brand name Daraprim among others, is a medication used with leucovorin to treat the parasitic diseases toxoplasmosis and cystoisosporiasis. It is also used with dapsone as a second-line option to prevent Pneumocystis jiroveci pneumonia in people with HIV/AIDS. It was previously used for malaria but is no longer recommended due to resistance. Pyrimethamine is taken by mouth.

<span class="mw-page-title-main">GTP cyclohydrolase I</span>

GTP cyclohydrolase I (GTPCH) (EC 3.5.4.16) is a member of the GTP cyclohydrolase family of enzymes. GTPCH is part of the folate and biopterin biosynthesis pathways. It is responsible for the hydrolysis of guanosine triphosphate (GTP) to form 7,8-dihydroneopterin triphosphate (7,8-DHNP-3'-TP, 7,8-NH2-3'-TP).

<span class="mw-page-title-main">Sulfanilamide</span> Chemical compound

Sulfanilamide is a sulfonamide antibacterial drug. Chemically, it is an organic compound consisting of an aniline derivatized with a sulfonamide group. Powdered sulfanilamide was used by the Allies in World War II to reduce infection rates and contributed to a dramatic reduction in mortality rates compared to previous wars. Sulfanilamide is rarely if ever used systemically due to toxicity and because more effective sulfonamides are available for this purpose. Modern antibiotics have supplanted sulfanilamide on the battlefield; however, sulfanilamide remains in use today in the form of topical preparations, primarily for treatment of vaginal yeast infections mainly vulvovaginitis which is caused by Candida albicans.

<span class="mw-page-title-main">Sulfacetamide</span> Sulfonamide antibiotic

Sulfacetamide is a sulfonamide antibiotic.

<span class="mw-page-title-main">Dihydropteroate</span> Chemical compound

Dihydropteroate is an important intermediate in folate synthesis. It is a pterin created from para-aminobenzoic acid (PABA) by the enzyme dihydropteroate synthase.

<span class="mw-page-title-main">Tetrahydrofolic acid</span> Chemical compound

Tetrahydrofolic acid (THFA), or tetrahydrofolate, is a folic acid derivative.

<span class="mw-page-title-main">Sulfadimethoxine</span> Chemical compound

Sulfadimethoxine is a long-lasting sulfonamide antimicrobial medication used in veterinary medicine. It is used to treat many infections, including respiratory, urinary tract, enteric, and soft tissue infections and can be given as a standalone or combined with ormetoprim to broaden the target range. Like all sulfamides, sulfadimethoxine inhibits bacterial synthesis of folic acid by acting as a competitive inhibitor against PABA. It is the most common drug prescribed to dogs who have coccidiosis.

<span class="mw-page-title-main">Antifolate</span> Class of antimetabolite medications

Antifolates are a class of antimetabolite medications that antagonise (that is, block) the actions of folic acid (vitamin B9). Folic acid's primary function in the body is as a cofactor to various methyltransferases involved in serine, methionine, thymidine and purine biosynthesis. Consequently, antifolates inhibit cell division, DNA/RNA synthesis and repair and protein synthesis. Some such as proguanil, pyrimethamine and trimethoprim selectively inhibit folate's actions in microbial organisms such as bacteria, protozoa and fungi. The majority of antifolates work by inhibiting dihydrofolate reductase (DHFR).

<span class="mw-page-title-main">Dihydroneopterin aldolase</span>

The enzyme dihydroneopterin aldolase catalyzes the chemical reaction

<span class="mw-page-title-main">Aminodeoxychorismate synthase</span>

In enzymology, an aminodeoxychorismate synthase is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">Dihydrofolate synthase</span> Class of enzymes

In enzymology, a dihydrofolate synthase is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">2-amino-4-hydroxy-6-hydroxymethyldihydropteridine diphosphokinase</span> Enzyme

In enzymology, a 2-amino-4-hydroxy-6-hydroxymethyldihydropteridine diphosphokinase is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">Dihydropteroate synthase inhibitor</span> A drug that inhibits the action of dihydropteroate synthase

Dihydropteroate synthase inhibitors are drugs that inhibit the action of dihydropteroate synthase. They include sulfonamides, dapsone, and para-aminosalicylic acid.

Phytoene synthase is a transferase enzyme involved in the biosynthesis of carotenoids. It catalyzes the conversion of geranylgeranyl pyrophosphate to phytoene. This enzyme catalyses the following chemical reaction

Geranyl diphosphate 2-C-methyltransferase is an enzyme with systematic name S-adenosyl-L-methionine:geranyl-diphosphate 2-C-methyltransferase. This enzyme catalyses the following chemical reaction

<span class="mw-page-title-main">Ketoacyl synthase</span> Catalyst for a key step in fatty acid synthesis

Ketoacyl synthases (KSs) catalyze the condensation reaction of acyl-CoA or acyl-acyl ACP with malonyl-CoA to form 3-ketoacyl-CoA or with malonyl-ACP to form 3-ketoacyl-ACP. This reaction is a key step in the fatty acid synthesis cycle, as the resulting acyl chain is two carbon atoms longer than before. KSs exist as individual enzymes, as they do in type II fatty acid synthesis and type II polyketide synthesis, or as domains in large multidomain enzymes, such as type I fatty acid synthases (FASs) and polyketide synthases (PKSs). KSs are divided into five families: KS1, KS2, KS3, KS4, and KS5.

References

  1. Universal protein resource accession number Q46389 at UniProt.
  2. 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. doi:10.1128/jb.172.12.7211-7226.1990. PMC   210846 . PMID   2123867.
  3. 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.
This article incorporates text from the public domain Pfam and InterPro: IPR000489