Folylpolyglutamate synthase - Revision history

Michal Harel at 11:20, 9 January 2023

Michal Harel — Mon, 09 Jan 2023 11:20:54 GMT

←Older revision		Revision as of 11:20, 9 January 2023
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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 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.	+	[[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 ==		== Function ==

Karsten Theis at 23:09, 14 April 2022

Karsten Theis — Thu, 14 Apr 2022 23:09:25 GMT

←Older revision		Revision as of 23:09, 14 April 2022
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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 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 ==		== Function ==
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	[[Category:Topic Page]]		[[Category:Topic Page]]
	[[Category:Tetrahydrofolate]]		[[Category:Tetrahydrofolate]]
		+	[[Category:One-carbon metabolism]]

Karsten Theis: /* Function */

Karsten Theis — Wed, 13 Apr 2022 02:06:09 GMT

Function

←Older revision		Revision as of 02:06, 13 April 2022
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	== Function ==		== 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, ~~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. Apart from 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.	+	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.

	[[Image:Tetrahydrofolate synthase hydrolase.PNG\|600px]]		[[Image:Tetrahydrofolate synthase hydrolase.PNG\|600px]]

Karsten Theis: /* Structure */

Karsten Theis — Wed, 13 Apr 2022 01:58:48 GMT

Structure

←Older revision		Revision as of 01:58, 13 April 2022
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	{{Template:Button Toggle Animation2}}		{{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 ~~where~~ all three substrates ~~are~~ bound simultaneously ~~yet~~.	+	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>.		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>.

Karsten Theis: /* Structure */

Karsten Theis — Wed, 13 Apr 2022 01:55:35 GMT

Structure

←Older revision		Revision as of 01:55, 13 April 2022
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	==Structure==		==Structure==
	<StructureSection load='' size='400' side='right' caption='' scene='74/748269/Cv/7'>		<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/4'>conformational change</scene> into the active form.	+	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}}		{{Template:Button Toggle Animation2}}

-	The <scene name='74/748269/Glu/2'>Yersinia pestis structure</scene> 3qcz, shows glutamate bound near ATP while the folate binding site is empty. There is no structure where all three substrates are bound simultaneously yet.	+	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 where all three substrates are bound simultaneously yet.

	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>.		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>.

Karsten Theis: /* Structure */

Karsten Theis — Wed, 13 Apr 2022 01:51:14 GMT

Structure

←Older revision		Revision as of 01:51, 13 April 2022
Line 11:		Line 11:
	==Structure==		==Structure==
	<StructureSection load='' size='400' side='right' caption='' scene='74/748269/Cv/7'>		<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/1'>folate is bound</scene>, the enzyme undergoes a <scene name='74/748269/Folate_binding/4'>conformational change</scene> into the active form.	+	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/4'>conformational change</scene> into the active form.
	{{Template:Button Toggle Animation2}}		{{Template:Button Toggle Animation2}}

-	The <scene name='74/748269/Glu/1'>Yersinia pestis structure</scene> 3qcz, shows glutamate bound near ATP while the folate binding site is empty. There is no structure where all three substrates are bound simultaneously yet.	+	The <scene name='74/748269/Glu/2'>Yersinia pestis structure</scene> 3qcz, shows glutamate bound near ATP while the folate binding site is empty. There is no structure where all three substrates are bound simultaneously yet.

	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>.		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>.

Karsten Theis at 01:41, 13 April 2022

Karsten Theis — Wed, 13 Apr 2022 01:41:34 GMT

←Older revision		Revision as of 01:41, 13 April 2022
Line 11:		Line 11:
	==Structure==		==Structure==
	<StructureSection load='' size='400' side='right' caption='' scene='74/748269/Cv/7'>		<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~~. 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/4'>conformational change</scene> into the active form.	+	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/1'>folate is bound</scene>, the enzyme undergoes a <scene name='74/748269/Folate_binding/4'>conformational change</scene> into the active form.
	{{Template:Button Toggle Animation2}}		{{Template:Button Toggle Animation2}}

-	~~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.	+	The <scene name='74/748269/Glu/1'>Yersinia pestis structure</scene> 3qcz, shows glutamate bound near ATP while the folate binding site is empty. There is no structure where all three substrates are bound simultaneously yet.

-	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>~~. Water molecules shown as red spheres~~.	+	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>		</StructureSection>

Karsten Theis: /* Structure */

Karsten Theis — Tue, 12 Apr 2022 21:35:36 GMT

Structure

←Older revision		Revision as of 21:35, 12 April 2022
Line 11:		Line 11:
	==Structure==		==Structure==
	<StructureSection load='' size='400' side='right' caption='' scene='74/748269/Cv/7'>		<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. 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/3'>conformational change</scene> into the active form.	+	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. 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/4'>conformational change</scene> into the active form.
	{{Template:Button Toggle Animation2}}		{{Template:Button Toggle Animation2}}

Karsten Theis: /* Structure */

Karsten Theis — Tue, 12 Apr 2022 21:19:10 GMT

Structure

←Older revision		Revision as of 21:19, 12 April 2022
Line 11:		Line 11:
	==Structure==		==Structure==
	<StructureSection load='' size='400' side='right' caption='' scene='74/748269/Cv/7'>		<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. 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.	+	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. 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/3'>conformational change</scene> into the active form.
		+	{{Template:Button Toggle Animation2}}
		+
		+	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.

	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>. Water molecules shown as red spheres.		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>. Water molecules shown as red spheres.

Karsten Theis: /* Structure */

Karsten Theis — Tue, 12 Apr 2022 14:49:12 GMT

Structure

←Older revision		Revision as of 14:49, 12 April 2022
Line 11:		Line 11:
	==Structure==		==Structure==
	<StructureSection load='' size='400' side='right' caption='' scene='74/748269/Cv/7'>		<StructureSection load='' size='400' side='right' caption='' scene='74/748269/Cv/7'>
-	Folylpolyglutamate synthase is a single subunit enzyme with two domains. 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. 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.	+	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. 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.

	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>. Water molecules shown as red spheres.		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>. Water molecules shown as red spheres.