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<StructureSection load='2vor' size='400' side='right' caption='Folypolyglutamate synthase complex with ADP, AMPPCP and Co+2 ion (pink) (PDB code [[2vor]])' scene='74/748269/Cv/1'>
[[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 effective, 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 ==
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; before the amide bond forms, the carboxylate reacts with ATP to form a phosphate ester intermediate and ADP. In the second step, phosphate is the leaving group as the amide bond forms. The deconjugation reaction (i.e. removing glutamate units) is catalyzed by a hydrolase (folate gamma-glutamyl hydrolase, or GGH) and proceeds independent of ATP. Apart from reacting with various folates, FPGS also acts on anti-folates (competitive inhibitores of enzymes that act of folates). The polyglutaminylation of anti-folates makes them effective inhibitors.


== Function ==
[[Image:Tetrahydrofolate synthase hydrolase.PNG|600px]]
'''Folypolyglutamate synthase''' (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>.
 
== 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.
 
==Structure==
<StructureSection load='' size='400' side='right' caption='' scene='74/748269/Cv/7'>
Folylpolyglutamate synthase is a single subunit enzyme with two domains (reload <scene name='74/748269/Cv/7'>initial scene</scene>). The three substrates (folate, ATP, glutamate) bind on the same face in a <scene name='74/748269/Conserved/1'>highly conserved patch</scene> near the domain boundary. Once <scene name='74/748269/Folate/2'>folate is bound</scene>, the enzyme undergoes a <scene name='74/748269/Folate_binding/5'>conformational change</scene> into the active form.
{{Template:Button Toggle Animation2}}
 
The <scene name='74/748269/Glu/3'>Yersinia pestis structure</scene> 3qcz, shows glutamate bound near ATP while the folate binding site is empty. There is no structure yet with all three substrates bound simultaneously.
 
The nucleotide-binding pocket of FPGS occupies a <scene name='74/748269/Cv/4'>narrow channel between the N- and C-terminal domains</scene> of the protein and <scene name='74/748269/Cv/6'>contains the nucleotide and a divalent ion</scene><ref>PMID:18566510</ref>.
</StructureSection>


== Disease ==
== Disease ==
Mutations in FPGS are associated with increased childhood acute lymphoblastic leukemia<ref>PMID:26107232</ref>.
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>.
== Relevance ==
 
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>


== Structural highlights ==
Synthesis of folate<ref>DOI:10.1186/1471-2164-8-245</ref>
The nucleotide -binding pocket of FPGS occupies a narrow channel between the N- and C-terminal domains of the protein and contains the nucleotide and a divalent ion<ref>PMID:18566510</ref>.
==3D structures of folylpolyglutamate synthase==
</StructureSection>
==3D structures of folypolyglutamate synthase==


Updated on {{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}
Updated on {{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}
{{#tree:id=OrganizedByTopic|openlevels=0|
{{#tree:id=OrganizedByTopic|openlevels=0|


*Folypolyglutamate synthase  
*Folylpolyglutamate synthase  


**[[3nrs]] – YpFPGS/dihydrofolate synthase – Yersinia pestis  <BR />
**[[3nrs]] – YpFPGS/dihydrofolate synthase – ''Yersinia pestis'' <BR />
**[[1o5z]] – FPGS – Thermotoga maritima  <BR />
**[[1o5z]] – FPGS – ''Thermotoga maritima'' <BR />
**[[2gca]] – LcFPGS – Lactobacillus casei  <BR />
**[[2gca]] – LcFPGS – ''Lactobacillus casei'' <BR />
**[[6k8c]] – FPGS – ''Helicobacter pylori'' <BR />


*Folypolyglutamate synthase complex
*Folylpolyglutamate synthase complex


**[[3qcz]] – YpFPGS/dihydrofolate synthase + AMPPNP + Mn + glutamate  <BR />
**[[3qcz]] – YpFPGS/dihydrofolate synthase + AMPPNP + Mn + glutamate  <BR />
**[[3pyz]] – YpFPGS/dihydrofolate synthase + AMPPNP + Mn  <BR />
**[[3pyz]] – YpFPGS/dihydrofolate synthase + AMPPNP + Mn  <BR />
**[[3n2a]] – YpFPGS/dihydrofolate synthase + ADP + Mg  <BR />
**[[3n2a]] – YpFPGS/dihydrofolate synthase + ADP + Mg  <BR />
**[[2vor]] – MtFPGS + ADP + AMPPNP – Mycobacterium tuberculosis  <BR />
**[[2vor]] – MtFPGS + ADP + AMPPNP – ''Mycobacterium tuberculosis'' <BR />
**[[2vos]] – MtFPGS + ADP  <BR />
**[[2vos]] – MtFPGS + ADP  <BR />
**[[2gc5]], [[2gc6]], [[2gcb]] – FPGS (mutant)  <BR />
**[[2gc5]], [[2gc6]], [[2gcb]] – FPGS (mutant)  <BR />
**[[1w78]] – EcFPGS + ADP + DHPP – Escherichia coli <BR />
**[[1w78]] – EcFPGS + ADP + DHPP – ''Escherichia coli'' <BR />
**[[1w7k]] – EcFPGS + ADP  <BR />
**[[1w7k]] – EcFPGS + ADP  <BR />
**[[1jbv]] – LcFPGS + AMPPCP  <BR />
**[[1jbv]] – LcFPGS + AMPPCP  <BR />
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== References ==
== References ==
<references/>
<references/>
[[Category:Topic Page]]
[[Category:Tetrahydrofolate]]
[[Category:One-carbon metabolism]]

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

Michal Harel, Jaime Prilusky, Alexander Berchansky, Joel L. Sussman, Karsten Theis
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