Dihydropteroate synthase
| Dihydropteroate synthetase | |||||||||
|---|---|---|---|---|---|---|---|---|---|
 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 | ||||||||
| |||||||||
Dihydropteroate synthase (DHPS) is an enzyme classified under EC 2.5.1.15. It catalyzes a condensation reaction:
- (2-amino-4-hydroxy-7,8-dihydropteridin-6-yl)methyl diphosphate + 4-aminobenzoate (PABA) diphosphate + dihydropteroate.
This reaction produces dihydropteroate. DHPS is found in archaea, bacteria, some protozoans, fungi, and plants, but not in animals. In non-archaeal organisms, this enzyme participates in folate biosynthesis. In archaea, this enzyme participates in methanopterin biosynthesis. All organisms require a reduced folate/methanopterin cofactor for their one-carbon metabolism. Most microorganisms must synthesize folate de novo because they lack the active transport system of animal cells that allows these organisms to use preformed folates.[a]
The nonexistence of DHPS in humans (and its essential role in other organisms) makes it a useful target for sulfonamide antibiotics, which compete with the PABA precursor (see dihydropteroate synthase inhibitor). All organisms require reduced folate cofactors
Examples
[edit]Bacterial DHPS (gene sul or folP)[3] 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) with 2-amino-4-hydroxy-6-hydroxymethyldihydropteridine diphosphokinase (HPPK).[4] A similar arrangement is found in the model plant Arabidopsis thaliana.[5] DHPS is the target of the herbicide asulam.[6]
The Saccharomyces cerevisiae (baker's yeast, a fungus) version is trifunctional: the enzyme has DHPS, HPPK, and dihydroneopterin aldolase.[5]
Protein domain
[edit]| Pterin binding enzyme | |||||||
|---|---|---|---|---|---|---|---|
| Identifiers | |||||||
| Symbol | Pterin_bind | ||||||
| Pfam | PF00809 | ||||||
| InterPro | IPR000489 | ||||||
| PROSITE | PDOC00630 | ||||||
| SCOP2 | 1ajz / SCOPe / SUPFAM | ||||||
| |||||||
Proteins containing the pterin-binding enzyme domain include dihydropteroate synthase (EC 2.5.1.15) as well as a group of methyltransferase enzymes including 5-Methyltetrahydrofolate:corrinoid/iron-sulfur protein Co-methyltransferase (MeTr)[7] that catalyses a key step in the Wood-Ljungdahl pathway of carbon dioxide fixation.
References
[edit]- ^ Some invertebrates such as C. elegans only have a transporter for reduced folate (i.e. THF, folinic acid, etc.), not oxidized folate, the main form found in food. They can nevertheless make use of oxidized folate by having it break down spontaneously to PABA-glu, which E. coli can turn into PABA intracellularly thanks to a specialized transporter. The THF produced by E. coli is then picked up by the reduced-folate transporter.[1] In contrast, humans can directly use oxidized folates thanks to the proton-coupled folate transporter and have no need for this detour.[2]
- ^ Maynard, C; Cummins, I; Green, J; Weinkove, D (15 June 2018). "A bacterial route for folic acid supplementation". BMC biology. 16 (1): 67. doi:10.1186/s12915-018-0534-3. PMID 29903004.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ Desmoulin, SK; Hou, Z; Gangjee, A; Matherly, LH (December 2012). "The human proton-coupled folate transporter: Biology and therapeutic applications to cancer". Cancer biology & therapy. 13 (14): 1355–73. doi:10.4161/cbt.22020. PMID 22954694.
- ^ 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.
- ^ 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.
- ^ a b https://enzyme.expasy.org/EC/2.5.1.15 (specifically, in IUBMB commentary).
- ^ Vadlamani, Grishma; Sukhoverkov, Kirill V.; Haywood, Joel; Breese, Karen J.; Fisher, Mark F.; Stubbs, Keith A.; Bond, Charles S.; Mylne, Joshua S. (July 2022). "Crystal structure of Arabidopsis thaliana HPPK/DHPS, a bifunctional enzyme and target of the herbicide asulam". Plant Communications. 3 (4) 100322. doi:10.1016/j.xplc.2022.100322.
- ^ Universal protein resource accession number Q46389 at UniProt.
External links
[edit]- Dihydropteroate+synthetase at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
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