Folylpolyglutamate synthase: Difference between revisions
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[[Folylpolyglutamate synthase]] or synthetase (FPGS) attaches gamma-glutamate units to various forms of folate (vitamin B9). In eukaryotic organisms, polyglutamylation keeps folate in the compartment, while folate lacking it can travel to other compartments. To be effecitive, antifolates (competitive inhibitors whose structure is similar to tetrahydrofolate) have to undergo polyglutamylation as well. Thus, defects in FPGS have consequences for the one-carbon metabolism relying on availability of folate as well as treatment of cancer relying on antifolates. | [[Folylpolyglutamate synthase]] or synthetase (FPGS) attaches gamma-glutamate units to various forms of folate (vitamin B9). In eukaryotic organisms, polyglutamylation keeps folate in the compartment, while folate lacking it can travel to other compartments. To be effecitive, antifolates (competitive inhibitors whose structure is similar to tetrahydrofolate) have to undergo polyglutamylation as well. Thus, defects in FPGS have consequences for the one-carbon metabolism relying on availability of folate as well as treatment of cancer relying on antifolates. | ||
== | == Function == | ||
The enzyme catalyzes formation of an amide bond between the amino group of glutamate and the gamma carboxylate group of tetrahydrofolate (which contains a single glutamate unit) or of the free gamma carboxylate of the glumatamyl tail of polyglutamyl tetrahydrofolate. This reaction requires ATP, which ends up as ADP and phosphate after forming a covalent intermediate with the substrate ("activating" it). The hydrolysis reaction, catalyzed by a hydrolase, proceeds in absence of ATP. | FPGS is active in intracellular folate homeostasis. Polyglutamated folates are substrates for generation of the primary metyhl group donor S-adenosylmethionine (SAM)<ref>PMID:26895662</ref>, among others. The FPGS enzyme catalyzes formation of an amide bond between the amino group of glutamate and the gamma carboxylate group of tetrahydrofolate (which contains a single glutamate unit) or of the free gamma carboxylate of the glumatamyl tail of polyglutamyl tetrahydrofolate. This reaction requires ATP, which ends up as ADP and phosphate after forming a covalent intermediate with the substrate ("activating" it). The hydrolysis reaction, catalyzed by a hydrolase (folate gamma-glutamyl hydrolase, or GGH), proceeds in absence of ATP. | ||
[[Image:Tetrahydrofolate synthase hydrolase.PNG|600px]] | [[Image:Tetrahydrofolate synthase hydrolase.PNG|600px]] | ||
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== FPGS in different organisms == | == FPGS in different organisms == | ||
FPGS occurs in all kingdoms of life. In some organisms, the FPGS activity (EC [https://www.brenda-enzymes.org/enzyme.php?ecno=6.3.2.17 6.3.2.17]) is combined with adding a glutamate to dihydopteroate to form dihydrofolate (DHF synthase activity, EC [https://www.brenda-enzymes.org/enzyme.php?ecno=6.3.2.12 6.3.2.12]). The folC gene product of E. coli is one such combined enzyme. | FPGS occurs in all kingdoms of life. In some organisms, the FPGS activity (EC [https://www.brenda-enzymes.org/enzyme.php?ecno=6.3.2.17 6.3.2.17]) is combined with adding a glutamate to dihydopteroate to form dihydrofolate (DHF synthase activity, EC [https://www.brenda-enzymes.org/enzyme.php?ecno=6.3.2.12 6.3.2.12]). The folC gene product of E. coli is one such combined enzyme. | ||
==Structure== | ==Structure== | ||
<StructureSection load='' size='400' side='right' caption=' | <StructureSection load='' size='400' side='right' caption='' scene='74/748269/Cv/7'> | ||
FPGS binds to ATP, glutamate and folate (THF-(glu)n). Once <scene name='74/748269/Folate/1'>folate is bound</scene>, the enzyme undergoes a <scene name='74/748269/Folate_binding/2'>conformational change</scene> into the active form. In the <scene name='74/748269/Glu/1'>Yersinia pestis structure</scene> 3qcz, glutamate and ATP are bound but the folate binding site is empty. | FPGS binds to ATP, glutamate and folate (THF-(glu)n). Once <scene name='74/748269/Folate/1'>folate is bound</scene>, the enzyme undergoes a <scene name='74/748269/Folate_binding/2'>conformational change</scene> into the active form. In the <scene name='74/748269/Glu/1'>Yersinia pestis structure</scene> 3qcz, glutamate and ATP are bound but the folate binding site is empty. | ||
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</StructureSection> | </StructureSection> | ||
== | == Disease == | ||
Mutations in FPGS are associated with increased childhood acute lymphoblastic leukemia<ref>PMID:26107232</ref>. FPGS status is a predictor of chemosensitivity of colon cancer cells to 5-fluorouracil and methotrexate based chemotherapy and FPGS gene transfer may increase the sensitivity of colon cancer cells to 5-FU-based chemotherapy<ref>PMID:15542523</ref>. | |||
== | ==Further reading== | ||
* Cancer and FPGS <ref>DOI:10.1093/oxfordjournals.annonc.a059353</ref> | |||
* Rheumatoid arthritis<ref>DOI:10.1093/rheumatology/keaa428</ref> | |||
* Substrate binding and mechanism ([[1jbv]] and [[1jbw]]): <ref>DOI:10.1006/jmbi.2001.4815</ref> | |||
* Primary citation of [[1w78]] <ref>PMID:15705579</ref> | |||
Synthesis of folate<ref>DOI:10.1186/1471-2164-8-245</ref> | |||
==3D structures of folylpolyglutamate synthase== | ==3D structures of folylpolyglutamate synthase== | ||