6-deoxyerythronolide B synthase (DEBS) - Revision history

Michal Harel at 09:53, 19 May 2024

Michal Harel — Sun, 19 May 2024 09:53:58 GMT

←Older revision		Revision as of 09:53, 19 May 2024
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	<StructureSection load='' size='350' side='right' scene='40/400561/Ks-at_dimer/2' caption='6-deoxyerythronolide B synthase dimer [[2hg4]]'>		<StructureSection load='' size='350' side='right' scene='40/400561/Ks-at_dimer/2' caption='6-deoxyerythronolide B synthase dimer [[2hg4]]'>
	One of the '''[[CBI Molecules]]''' being studied in the [http://www.umass.edu/cbi/ University of Massachusetts Amherst Chemistry-Biology Interface Program] at UMass Amherst and on display at the [http://www.molecularplayground.org/ Molecular Playground].		One of the '''[[CBI Molecules]]''' being studied in the [http://www.umass.edu/cbi/ University of Massachusetts Amherst Chemistry-Biology Interface Program] at UMass Amherst and on display at the [http://www.molecularplayground.org/ Molecular Playground].
		+	__TOC__
		+	== Function ==

	Polyketides are a large and structurally diverse class of natural products produced by bacteria, fungi, and plants. They exhibit a wide variety of biological activities including antibiotic, antitumor, anticancer, among others.		Polyketides are a large and structurally diverse class of natural products produced by bacteria, fungi, and plants. They exhibit a wide variety of biological activities including antibiotic, antitumor, anticancer, among others.
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	After the extender unit is added, it can be further processed by optional tailoring domains, including ketoreductases (KRs), dehydratases (DHs), and enoyl reductases (ERs), to yield a hydroxyl, enoyl, or methylene group at the beta-position. Finally, the thioesterase (TE) domain that located at the C-terminus of DEBS module 6 promotes the macrocyclization event which releases the final product, 6-dEB. <ref>PMID:17328673</ref>		After the extender unit is added, it can be further processed by optional tailoring domains, including ketoreductases (KRs), dehydratases (DHs), and enoyl reductases (ERs), to yield a hydroxyl, enoyl, or methylene group at the beta-position. Finally, the thioesterase (TE) domain that located at the C-terminus of DEBS module 6 promotes the macrocyclization event which releases the final product, 6-dEB. <ref>PMID:17328673</ref>

-	===Ketosynthase-acyltransferase (KS-AT)===	+	==Ketosynthase-acyltransferase (KS-AT)==

	Molecular Playground banner: KS-AT The "builder" and the "gatekeeper".		Molecular Playground banner: KS-AT The "builder" and the "gatekeeper".
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	The KS accepts the "in-progress" polyketide from its upstream module, and then catalyzes the decarboxylative condensation of ACP-bound malonyl CoA derivatives with the in-progress chain. This results in an ACP-bound β-ketothioester which is processed by any other β-carbon tailoring domains present within the module.		The KS accepts the "in-progress" polyketide from its upstream module, and then catalyzes the decarboxylative condensation of ACP-bound malonyl CoA derivatives with the in-progress chain. This results in an ACP-bound β-ketothioester which is processed by any other β-carbon tailoring domains present within the module.

-	===Acyl Carrier Protein (ACP)===	+	==Acyl Carrier Protein (ACP)==
	Molecular Playground banner: "the communicator".		Molecular Playground banner: "the communicator".
	<scene name='6-deoxyerythronolide_B_synthase_(DEBS)/Cv/1'>Solution structure of acyl carrier protein domain from module 2 of 6-deoxyerythronolide B synthase (DEBS)</scene> ([[2ju1]]).		<scene name='6-deoxyerythronolide_B_synthase_(DEBS)/Cv/1'>Solution structure of acyl carrier protein domain from module 2 of 6-deoxyerythronolide B synthase (DEBS)</scene> ([[2ju1]]).
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-	=== Ketoreductase (KR) ===	+	== Ketoreductase (KR) ==
	The ketoreductase domain of a PKS is an optional tailoring domain that reduces a beta-ketoacyl ACP intermediate to the beta-hydroxy acyl ACP. <scene name='40/400561/Nadph/2'>NADPH</scene>, the co-factor for the KR domain, furnishes the hydride that is used in the reduction. The Erythromycin <scene name='55/559997/Kr/1'>KR domain</scene>		The ketoreductase domain of a PKS is an optional tailoring domain that reduces a beta-ketoacyl ACP intermediate to the beta-hydroxy acyl ACP. <scene name='40/400561/Nadph/2'>NADPH</scene>, the co-factor for the KR domain, furnishes the hydride that is used in the reduction. The Erythromycin <scene name='55/559997/Kr/1'>KR domain</scene>

-		+	==Dehydratase (DH)==
-		+
-	===Dehydratase (DH)===	+

	Molecular Playground banner: make modification on beta-keto-acyl-ACP, "the decorator".		Molecular Playground banner: make modification on beta-keto-acyl-ACP, "the decorator".
	<scene name='6-deoxyerythronolide_B_synthase_(DEBS)/Cv/2'>Crystal Structure of the dimeric Erythromycin Dehydratase monomer complex with sulfate and Cl- ion</scene> ([[3el6]]).		<scene name='6-deoxyerythronolide_B_synthase_(DEBS)/Cv/2'>Crystal Structure of the dimeric Erythromycin Dehydratase monomer complex with sulfate and Cl- ion</scene> ([[3el6]]).

-	===Thioesterase (TE)===	+	==Thioesterase (TE)==

	Molecular Playground banner: cyclize the molecule, "the closer".		Molecular Playground banner: cyclize the molecule, "the closer".

Michal Harel at 09:51, 19 May 2024

Michal Harel — Sun, 19 May 2024 09:51:39 GMT

←Older revision		Revision as of 09:51, 19 May 2024
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	[[Image:DEBS.png\|left\|500px\|thumb\|6-deoxyerythronolide B synthase (DEBS)]]		[[Image:DEBS.png\|left\|500px\|thumb\|6-deoxyerythronolide B synthase (DEBS)]]
	{{Clear}}		{{Clear}}
-	The '''6-deoxyerythronolide B synthase''' (DEBS), which catalyzes the formation of 6-dEB, consists of three large subunits, DEBS1, DEBS2 and DEBS3, each containing two modules and above 300 kD in size. There are 2 domains in the N-terminal loading module, responsible for priming the synthase with a proprionate starter unit, and 26 domains in the six extender modules, Each extender module contains at least three essential domains: a ketosynthase (KS), an acyl transferase (AT) and an acyl carrier protein (ACP). In detail, the AT domain selects the appropriate carbon extender unit and transfers the units from acyl-CoA onto the phosphopantetheine arm of ACP. The KSdomain accepts the polyketide chain from the previous module and catalyzes chain elongation reaction by adding an ACP-bound extender unit through decarboxylative condensation.	+	The '''6-deoxyerythronolide B synthase''' (DEBS), which catalyzes the formation of 6-dEB, consists of three large subunits, DEBS1, DEBS2 and DEBS3, each containing two modules and above 300 kD in size. There are 2 domains in the N-terminal loading module, responsible for priming the synthase with a proprionate starter unit, and 26 domains in the six extender modules, Each extender module contains at least three essential domains: a ketosynthase (KS), an acyl transferase (AT) and an acyl carrier protein (ACP). In detail, the AT domain selects the appropriate carbon extender unit and transfers the units from acyl-CoA onto the phosphopantetheine arm of ACP. The KSdomain accepts the polyketide chain from the previous module and catalyzes chain elongation reaction by adding an ACP-bound extender unit through decarboxylative condensation.<br />
		+
		+	'''DEBS1''' is acylated by a diketide at module 2<ref>PMID:8952473</ref>.<br />
		+	'''DEBS3''' carries out the final two cycles in the synthesis of 6-dEB<ref>PMID:9538011</ref>.

	After the extender unit is added, it can be further processed by optional tailoring domains, including ketoreductases (KRs), dehydratases (DHs), and enoyl reductases (ERs), to yield a hydroxyl, enoyl, or methylene group at the beta-position. Finally, the thioesterase (TE) domain that located at the C-terminus of DEBS module 6 promotes the macrocyclization event which releases the final product, 6-dEB. <ref>PMID:17328673</ref>		After the extender unit is added, it can be further processed by optional tailoring domains, including ketoreductases (KRs), dehydratases (DHs), and enoyl reductases (ERs), to yield a hydroxyl, enoyl, or methylene group at the beta-position. Finally, the thioesterase (TE) domain that located at the C-terminus of DEBS module 6 promotes the macrocyclization event which releases the final product, 6-dEB. <ref>PMID:17328673</ref>

Michal Harel at 09:36, 19 May 2024

Michal Harel — Sun, 19 May 2024 09:36:47 GMT

←Older revision		Revision as of 09:36, 19 May 2024
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	[[Image:DEBS.png\|left\|500px\|thumb\|6-deoxyerythronolide B synthase (DEBS)]]		[[Image:DEBS.png\|left\|500px\|thumb\|6-deoxyerythronolide B synthase (DEBS)]]
	{{Clear}}		{{Clear}}
-	The 6-deoxyerythronolide B synthase (DEBS), which catalyzes the formation of 6-dEB, consists of three large subunits, DEBS1, DEBS2 and DEBS3, each containing two modules and above 300 kD in size. There are 2 domains in the N-terminal loading module, responsible for priming the synthase with a proprionate starter unit, and 26 domains in the six extender modules, Each extender module contains at least three essential domains: a ketosynthase (KS), an acyl transferase (AT) and an acyl carrier protein (ACP). In detail, the AT domain selects the appropriate carbon extender unit and transfers the units from acyl-CoA onto the phosphopantetheine arm of ACP. The KSdomain accepts the polyketide chain from the previous module and catalyzes chain elongation reaction by adding an ACP-bound extender unit through decarboxylative condensation.	+	The '''6-deoxyerythronolide B synthase''' (DEBS), which catalyzes the formation of 6-dEB, consists of three large subunits, DEBS1, DEBS2 and DEBS3, each containing two modules and above 300 kD in size. There are 2 domains in the N-terminal loading module, responsible for priming the synthase with a proprionate starter unit, and 26 domains in the six extender modules, Each extender module contains at least three essential domains: a ketosynthase (KS), an acyl transferase (AT) and an acyl carrier protein (ACP). In detail, the AT domain selects the appropriate carbon extender unit and transfers the units from acyl-CoA onto the phosphopantetheine arm of ACP. The KSdomain accepts the polyketide chain from the previous module and catalyzes chain elongation reaction by adding an ACP-bound extender unit through decarboxylative condensation.

	After the extender unit is added, it can be further processed by optional tailoring domains, including ketoreductases (KRs), dehydratases (DHs), and enoyl reductases (ERs), to yield a hydroxyl, enoyl, or methylene group at the beta-position. Finally, the thioesterase (TE) domain that located at the C-terminus of DEBS module 6 promotes the macrocyclization event which releases the final product, 6-dEB. <ref>PMID:17328673</ref>		After the extender unit is added, it can be further processed by optional tailoring domains, including ketoreductases (KRs), dehydratases (DHs), and enoyl reductases (ERs), to yield a hydroxyl, enoyl, or methylene group at the beta-position. Finally, the thioesterase (TE) domain that located at the C-terminus of DEBS module 6 promotes the macrocyclization event which releases the final product, 6-dEB. <ref>PMID:17328673</ref>

Alexander Berchansky at 13:50, 28 October 2019

Alexander Berchansky — Mon, 28 Oct 2019 13:50:48 GMT

←Older revision		Revision as of 13:50, 28 October 2019
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	=== Ketoreductase (KR) ===		=== Ketoreductase (KR) ===
-	The ketoreductase domain of a PKS is an optional tailoring domain that reduces a beta-ketoacyl ACP intermediate to the beta-hydroxy acyl ACP. <scene name='40/400561/Nadph/2'>NADPH</scene>, the co-factor for the KR domain, furnishes the hydride that is used in the reduction.	+	The ketoreductase domain of a PKS is an optional tailoring domain that reduces a beta-ketoacyl ACP intermediate to the beta-hydroxy acyl ACP. <scene name='40/400561/Nadph/2'>NADPH</scene>, the co-factor for the KR domain, furnishes the hydride that is used in the reduction. The Erythromycin <scene name='55/559997/Kr/1'>KR domain</scene>
-	[[The Erythromycin ~~KR domain]]~~<scene name='55/559997/Kr/1'>KR domain</scene>	+

Michal Harel at 08:50, 21 February 2019

Michal Harel — Thu, 21 Feb 2019 08:50:35 GMT

←Older revision		Revision as of 08:50, 21 February 2019
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	</StructureSection>		</StructureSection>
-	==3D structures of 6-deoxyerythronolide B synthase==
-	Updated on {{REVISIONDAY2}}-{{MONTHNAME\|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}
-	{{#tree:id=OrganizedByTopic\|openlevels=0\|

-	*DEBS
-
-	**[[2hg4]] – yDEBS ketosynthase-acyltransferase didomain of module 5 - yeast <br />
-	**[[2qo3]] – SeDEBS module 3 – ''Sacchropolyspora erythraea''<br />
-	**[[6c9u]] – SeDEBS module 3 + antibody<br />
-	**[[6mlk]] – SeDEBS module 5,6 + antibody<br />
-
-	*DEBS1
-
-	**[[2ju1]], [[2ju2]] – yDEBS1 acyl carrier protein domain – NMR
-
-	*DEBS2
-
-	**[[3el6]] – yDEBS2 residues 2362-2653<br />
-	**[[1pzq]] – yDEBS2 C-terminal domain – NMR<br />
-	**[[1pzr]] – yDEBS2 C-terminal + yDEBS3 N-terminal – NMR
-
-	*DEBS3
-
-	**[[1mo2]] – yDEBS3 thioesterase domain<br />
-	**[[1kez]] – SeDEBS module 6 <br />
-	**[[5d3k]] – SeDEBS module 5-6 <br />
-	**[[5d3z]] – SeDEBS module 5-6 + inhibitor<br />
-
-	}}
	== References ==		== References ==
	<references/>		<references/>

Michal Harel at 08:44, 21 February 2019

Michal Harel — Thu, 21 Feb 2019 08:44:15 GMT

←Older revision		Revision as of 08:44, 21 February 2019
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	TE is the terminal domain in DEBS, releasing the completed polyketide from the synthase by forming a 14-membered lactone. It is able to close such a large ring by threading it into a large inner cavity which stabilizes its conformation while esterification occurs.		TE is the terminal domain in DEBS, releasing the completed polyketide from the synthase by forming a 14-membered lactone. It is able to close such a large ring by threading it into a large inner cavity which stabilizes its conformation while esterification occurs.
		+
		+	==3D structures of 6-deoxyerythronolide B synthase==
		+	[[6-deoxyerythronolide B synthase 3D structures]]
		+
	</StructureSection>		</StructureSection>
	==3D structures of 6-deoxyerythronolide B synthase==		==3D structures of 6-deoxyerythronolide B synthase==
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	**[[2hg4]] – yDEBS ketosynthase-acyltransferase didomain of module 5 - yeast <br />		**[[2hg4]] – yDEBS ketosynthase-acyltransferase didomain of module 5 - yeast <br />
	**[[2qo3]] – SeDEBS module 3 – ''Sacchropolyspora erythraea''<br />		**[[2qo3]] – SeDEBS module 3 – ''Sacchropolyspora erythraea''<br />
-		+	**[[6c9u]] – SeDEBS module 3 + antibody<br />
		+	**[[6mlk]] – SeDEBS module 5,6 + antibody<br />

	*DEBS1		*DEBS1

Alexander Berchansky at 09:31, 19 October 2017

Alexander Berchansky — Thu, 19 Oct 2017 09:31:05 GMT

←Older revision		Revision as of 09:31, 19 October 2017
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	Molecular Playground banner: KS-AT The "builder" and the "gatekeeper".		Molecular Playground banner: KS-AT The "builder" and the "gatekeeper".
	Structure of the homodimers of ketosynthase-acyltransferase didomain of module 5 from DEBS ([[2hg4]]).		Structure of the homodimers of ketosynthase-acyltransferase didomain of module 5 from DEBS ([[2hg4]]).
-	<scene name='40/400561/Ks-at_dimer/2'>KS-AT dimer</scene>	+	<scene name='40/400561/Ks-at_dimer/4'>KS-AT dimer</scene>
	The AT domain is responsible for selecting the building blocks which become incorporated into the polyketide chain, most often in the form of malonyl-CoA derivatives. Each polyketide synthase AT is exquisitely selective for one substrate type and the DEBS ATs are selective for (S)-methylmalonyl CoA. In this way it functions as the "gatekeeper", preventing erroneous building blocks from becoming incorporated into the growing chain. the methylmalonyl group is transferred by the AT to the ACP, from where it can become incorporated into the polyketide by the KS domain.		The AT domain is responsible for selecting the building blocks which become incorporated into the polyketide chain, most often in the form of malonyl-CoA derivatives. Each polyketide synthase AT is exquisitely selective for one substrate type and the DEBS ATs are selective for (S)-methylmalonyl CoA. In this way it functions as the "gatekeeper", preventing erroneous building blocks from becoming incorporated into the growing chain. the methylmalonyl group is transferred by the AT to the ACP, from where it can become incorporated into the polyketide by the KS domain.

Alexander Berchansky at 09:28, 19 October 2017

Alexander Berchansky — Thu, 19 Oct 2017 09:28:59 GMT

←Older revision		Revision as of 09:28, 19 October 2017
Line 16:		Line 16:
	Molecular Playground banner: KS-AT The "builder" and the "gatekeeper".		Molecular Playground banner: KS-AT The "builder" and the "gatekeeper".
	Structure of the homodimers of ketosynthase-acyltransferase didomain of module 5 from DEBS ([[2hg4]]).		Structure of the homodimers of ketosynthase-acyltransferase didomain of module 5 from DEBS ([[2hg4]]).
-	<scene name='~~User:Tsung-Yi_Lin~~/~~6-deoxyerythronolide_B_synthase~~/Ks-at_dimer/2'>KS-AT dimer</scene>	+	<scene name='40/400561/Ks-at_dimer/2'>KS-AT dimer</scene>
	The AT domain is responsible for selecting the building blocks which become incorporated into the polyketide chain, most often in the form of malonyl-CoA derivatives. Each polyketide synthase AT is exquisitely selective for one substrate type and the DEBS ATs are selective for (S)-methylmalonyl CoA. In this way it functions as the "gatekeeper", preventing erroneous building blocks from becoming incorporated into the growing chain. the methylmalonyl group is transferred by the AT to the ACP, from where it can become incorporated into the polyketide by the KS domain.		The AT domain is responsible for selecting the building blocks which become incorporated into the polyketide chain, most often in the form of malonyl-CoA derivatives. Each polyketide synthase AT is exquisitely selective for one substrate type and the DEBS ATs are selective for (S)-methylmalonyl CoA. In this way it functions as the "gatekeeper", preventing erroneous building blocks from becoming incorporated into the growing chain. the methylmalonyl group is transferred by the AT to the ACP, from where it can become incorporated into the polyketide by the KS domain.

Alexander Berchansky at 09:23, 19 October 2017

Alexander Berchansky — Thu, 19 Oct 2017 09:23:16 GMT

←Older revision		Revision as of 09:23, 19 October 2017
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-	<StructureSection load='' size='350' side='right' scene='40/400561/Ks-at_dimer/2' caption='6-~~deoxyerythronolide_B_synthase~~ dimer [[2hg4]]'>	+	<StructureSection load='' size='350' side='right' scene='40/400561/Ks-at_dimer/2' caption='6-deoxyerythronolide B synthase dimer [[2hg4]]'>
	One of the '''[[CBI Molecules]]''' being studied in the [http://www.umass.edu/cbi/ University of Massachusetts Amherst Chemistry-Biology Interface Program] at UMass Amherst and on display at the [http://www.molecularplayground.org/ Molecular Playground].		One of the '''[[CBI Molecules]]''' being studied in the [http://www.umass.edu/cbi/ University of Massachusetts Amherst Chemistry-Biology Interface Program] at UMass Amherst and on display at the [http://www.molecularplayground.org/ Molecular Playground].

Joel L. Sussman at 20:25, 18 October 2017

Joel L. Sussman — Wed, 18 Oct 2017 20:25:44 GMT

←Older revision		Revision as of 20:25, 18 October 2017
Line 1:		Line 1:
-	<StructureSection load='' size='350' side='right' scene='40/400561/Ks-at_dimer/1' caption='6-deoxyerythronolide_B_synthase dimer [[2hg4]]'>	+	<StructureSection load='' size='350' side='right' scene='40/400561/Ks-at_dimer/2' caption='6-deoxyerythronolide_B_synthase dimer [[2hg4]]'>
	One of the '''[[CBI Molecules]]''' being studied in the [http://www.umass.edu/cbi/ University of Massachusetts Amherst Chemistry-Biology Interface Program] at UMass Amherst and on display at the [http://www.molecularplayground.org/ Molecular Playground].		One of the '''[[CBI Molecules]]''' being studied in the [http://www.umass.edu/cbi/ University of Massachusetts Amherst Chemistry-Biology Interface Program] at UMass Amherst and on display at the [http://www.molecularplayground.org/ Molecular Playground].