6nkh - Revision history

OCA at 14:48, 13 March 2024

OCA — Wed, 13 Mar 2024 14:48:06 GMT

←Older revision		Revision as of 14:48, 13 March 2024
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	<StructureSection load='6nkh' size='340' side='right'caption='[[6nkh]], [[Resolution\|resolution]] 1.60Å' scene=''>		<StructureSection load='6nkh' size='340' side='right'caption='[[6nkh]], [[Resolution\|resolution]] 1.60Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[6nkh]] is a 4 chain structure with sequence from [~~http~~://en.wikipedia.org/wiki/~~Atcc_34524 Atcc 34524~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6NKH OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=6NKH FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6nkh]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Malbranchea_aurantiaca Malbranchea aurantiaca]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6NKH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6NKH FirstGlance]. <br>
-	</td></tr><tr id='~~gene~~'><td class="sblockLbl"><b>[[~~Gene~~\|~~Gene~~:]]</b></td><td class="sblockDat">~~malC (~~[~~http://www~~.~~ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info~~&~~srchmode=5&id=78605 ATCC 34524])~~</td></tr>	+	</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models\|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution\|Resolution]] 1.6Å</td></tr>
-	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=6nkh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6nkh OCA], [~~http~~://pdbe.org/6nkh PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=6nkh RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/6nkh PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=6nkh ProSAT]</span></td></tr>	+	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6nkh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6nkh OCA], [https://pdbe.org/6nkh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6nkh RCSB], [https://www.ebi.ac.uk/pdbsum/6nkh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6nkh ProSAT]</span></td></tr>
	</table>		</table>
-	~~<div style~~=~~"background-color:#fffaf0;">~~	+	== Function ==
-	=~~= Publication Abstract from PubMed~~ ==	+	[https://www.uniprot.org/uniprot/MALC_MALAU MALC_MALAU] Short-chain dehydrogenase/reductase; part of the gene cluster that mediates the biosynthesis of malbrancheamide, a dichlorinated fungal indole alkaloid that belongs to a family of natural products containing a characteristic bicyclo[2.2.2]diazaoctane core (PubMed:23213353, PubMed:28777910, PubMed:31548667). The first step of malbrancheamide biosynthesis involves coupling of L-proline and L-tryptophan by malG, a bimodular NRPS, to produce L-Pro-L-Trp aldehyde through reductive offloading (PubMed:23213353, PubMed:31548667). This compound undergoes spontaneous cyclization and dehydration to give a dienamine which is reverse prenylated at C-2 by malE (PubMed:31548667). The other prenyltransferase present in the cluster, malB, displays modest activity, suggesting that may be a redundant gene in the pathway (PubMed:31548667). Subsequently, a [4+2] Diels-Alder cyclo-addition catalyzed by the bifunctional enzyme malC forms the characteristic bicyclo[2.2.2]diazaoctane ring of premalbrancheamid (PubMed:31548667). The first reaction catalyzed is a NADPH-dependent reduction reaction in which the nicotinamide cofactor is a stoichiometric reagent (PubMed:31548667). Either NADH or NADPH is effective as a cofactor (PubMed:31548667). Finally, the flavin-dependent halogenase malA catalyzes the iterative dichlorination of the indole ring of premalbrancheamide to yield C-9 monochlorinated malbrancheamide B, C-8 monochlorinated isomalbrancheamide B, and dichlorinated malbrancheamide (PubMed:28777910, PubMed:31548667). MalA is also able to brominate premalbrancheamide at C-9 to yield malbrancheamide C, and, to a lesser extend, at C-8 to yield isomalbrancheamide C (PubMed:28777910). Finally, malA can brominate C-9 monochlorinated malbrancheamide B at C-8 to yield malbrancheamide D, or C-8 monochlorinated isomalbrancheamide B at C-9 to produce isomalbrancheamide D (PubMed:28777910).<ref>PMID:23213353</ref> <ref>PMID:28777910</ref> <ref>PMID:31548667</ref>
-	~~Prenylated indole alkaloids such as the calmodulin~~-~~inhibitory malbrancheamides and anthelmintic paraherquamides possess great structural diversity and pharmaceutical utility. Here, we report complete elucidation~~ of the malbrancheamide ~~biosynthetic pathway accomplished through complementary approaches. These include~~ a ~~biomimetic total synthesis to access the natural~~ alkaloid ~~and biosynthetic intermediates in racemic form and in vitro enzymatic reconstitution~~ to ~~provide access to the~~ natural ~~antipode~~ (+)~~-malbrancheamide~~. ~~Reductive cleavage~~ of an L-Pro-L-Trp ~~dipeptide from the MalG non-ribosomal peptide synthetase~~ (~~NRPS~~) ~~followed by reverse prenylation~~ and a ~~cascade of post~~-~~NRPS reactions culminates~~ in ~~an intramolecular~~ [4+2] ~~hetero-~~Diels-Alder ~~(IMDA) cyclization to furnish~~ the bicyclo[2.2.2]diazaoctane ~~scaffold. Enzymatic assembly~~ of ~~optically pure~~ (+)~~-premalbrancheamide involves an unexpected zwitterionic intermediate where MalC catalyses enantioselective cycloaddition as~~ a ~~bifunctional~~ NADPH-dependent ~~reductase/Diels-Alderase~~. ~~The crystal structures of substrate and product complexes together with site-directed mutagenesis and molecular dynamics simulations demonstrate how MalC and PhqE~~ (~~its homologue from~~ the ~~paraherquamide pathway) catalyse diastereo~~- ~~and enantioselective cyclization in~~ the ~~construction~~ of ~~this important class of secondary metabolites.~~	+
-		+
-	~~Fungal~~ indole ~~alkaloid biogenesis through evolution~~ of ~~a bifunctional reductase/Diels~~-~~Alderase.~~,~~Dan Q~~, ~~Newmister SA~~, ~~Klas KR~~, ~~Fraley AE~~, ~~McAfoos TJ, Somoza AD, Sunderhaus JD~~, ~~Ye Y, Shende VV, Yu F, Sanders JN, Brown WC, Zhao L, Paton RS, Houk KN, Smith JL, Sherman DH, Williams RM Nat Chem. 2019 Sep 23. pii~~: 10.~~1038/s41557~~-~~019~~-~~0326-6. doi:~~, ~~10.1038/s41557~~-~~019~~-~~0326-6~~. ~~PMID:31548667~~<ref>PMID:~~31548667~~</ref>	+
-		+
-	~~From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.~~<br>	+
-	</~~div~~>	+
-	<~~div class="pdbe-citations 6nkh" style="background-color~~:~~#fffaf0;">~~</~~div~~>	+
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: Atcc 34524]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: ~~Dan, Q~~]]	+	[[Category: Malbranchea aurantiaca]]
-	[[Category: ~~Newmister, S A~~]]	+	[[Category: Dan Q]]
-	[[Category: ~~Sherman, D H~~]]	+	[[Category: Newmister SA]]
-	[[Category: ~~Smith, J L~~]]	+	[[Category: Sherman DH]]
-	[[Category: ~~Diels-alderase]]~~	+	[[Category: Smith JL]]
-	~~[[Category: Oxidoreductase]]~~	+
-	~~[[Category: Reductase~~]]	+

OCA at 08:26, 6 November 2019

OCA — Wed, 06 Nov 2019 08:26:54 GMT

←Older revision		Revision as of 08:26, 6 November 2019
Line 3:		Line 3:
	<StructureSection load='6nkh' size='340' side='right'caption='[[6nkh]], [[Resolution\|resolution]] 1.60Å' scene=''>		<StructureSection load='6nkh' size='340' side='right'caption='[[6nkh]], [[Resolution\|resolution]] 1.60Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[6nkh]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6NKH OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6NKH FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6nkh]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Atcc_34524 Atcc 34524]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6NKH OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6NKH FirstGlance]. <br>
-	</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6nkh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6nkh OCA], [http://pdbe.org/6nkh PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6nkh RCSB], [http://www.ebi.ac.uk/pdbsum/6nkh PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6nkh ProSAT]</span></td></tr>	+	</td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">malC ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=78605 ATCC 34524])</td></tr>
		+	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6nkh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6nkh OCA], [http://pdbe.org/6nkh PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6nkh RCSB], [http://www.ebi.ac.uk/pdbsum/6nkh PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6nkh ProSAT]</span></td></tr>
	</table>		</table>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
Line 19:		Line 20:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Atcc 34524]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
	[[Category: Dan, Q]]		[[Category: Dan, Q]]

OCA at 05:20, 10 October 2019

OCA — Thu, 10 Oct 2019 05:20:28 GMT

←Older revision		Revision as of 05:20, 10 October 2019
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 6nkh is ~~ON HOLD until Paper~~ Publication	+	==Structure of MalC Reductase/Diels-Alderase from Malbranchea aurantiaca==
		+	<StructureSection load='6nkh' size='340' side='right'caption='[[6nkh]], [[Resolution\|resolution]] 1.60Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[6nkh]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6NKH OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6NKH FirstGlance]. <br>
		+	</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6nkh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6nkh OCA], [http://pdbe.org/6nkh PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6nkh RCSB], [http://www.ebi.ac.uk/pdbsum/6nkh PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6nkh ProSAT]</span></td></tr>
		+	</table>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Prenylated indole alkaloids such as the calmodulin-inhibitory malbrancheamides and anthelmintic paraherquamides possess great structural diversity and pharmaceutical utility. Here, we report complete elucidation of the malbrancheamide biosynthetic pathway accomplished through complementary approaches. These include a biomimetic total synthesis to access the natural alkaloid and biosynthetic intermediates in racemic form and in vitro enzymatic reconstitution to provide access to the natural antipode (+)-malbrancheamide. Reductive cleavage of an L-Pro-L-Trp dipeptide from the MalG non-ribosomal peptide synthetase (NRPS) followed by reverse prenylation and a cascade of post-NRPS reactions culminates in an intramolecular [4+2] hetero-Diels-Alder (IMDA) cyclization to furnish the bicyclo[2.2.2]diazaoctane scaffold. Enzymatic assembly of optically pure (+)-premalbrancheamide involves an unexpected zwitterionic intermediate where MalC catalyses enantioselective cycloaddition as a bifunctional NADPH-dependent reductase/Diels-Alderase. The crystal structures of substrate and product complexes together with site-directed mutagenesis and molecular dynamics simulations demonstrate how MalC and PhqE (its homologue from the paraherquamide pathway) catalyse diastereo- and enantioselective cyclization in the construction of this important class of secondary metabolites.

-	~~Authors: Dan~~, Q., Newmister, ~~S.A.~~, ~~Smith~~, J.L., Sherman, D.H.	+	Fungal indole alkaloid biogenesis through evolution of a bifunctional reductase/Diels-Alderase.,Dan Q, Newmister SA, Klas KR, Fraley AE, McAfoos TJ, Somoza AD, Sunderhaus JD, Ye Y, Shende VV, Yu F, Sanders JN, Brown WC, Zhao L, Paton RS, Houk KN, Smith JL, Sherman DH, Williams RM Nat Chem. 2019 Sep 23. pii: 10.1038/s41557-019-0326-6. doi:, 10.1038/s41557-019-0326-6. PMID:31548667<ref>PMID:31548667</ref>

-	~~Description: Structure of MalC Reductase~~/~~Diels-Alderase from Malbranchea aurantiaca~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	~~[[Category: Unreleased Structures]]~~	+	</div>
-	~~[[Category: Newmister~~, S.~~A]]~~	+	<div class="pdbe-citations 6nkh" style="background-color:#fffaf0;"></div>
-	~~[[Category~~: ~~Smith, J.L]]~~	+	== References ==
-	[[Category: ~~Sherman, D.H~~]]	+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Large Structures]]
	[[Category: Dan, Q]]		[[Category: Dan, Q]]
		+	[[Category: Newmister, S A]]
		+	[[Category: Sherman, D H]]
		+	[[Category: Smith, J L]]
		+	[[Category: Diels-alderase]]
		+	[[Category: Oxidoreductase]]
		+	[[Category: Reductase]]

OCA at 05:05, 21 February 2019

OCA — Thu, 21 Feb 2019 05:05:42 GMT

←Older revision		Revision as of 05:05, 21 February 2019
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 6nkh is ON HOLD	+	The entry 6nkh is ON HOLD until Paper Publication

	Authors: Dan, Q., Newmister, S.A., Smith, J.L., Sherman, D.H.		Authors: Dan, Q., Newmister, S.A., Smith, J.L., Sherman, D.H.

OCA: Protected "6nkh" [edit=sysop:move=sysop]

OCA — Wed, 16 Jan 2019 10:41:47 GMT

Protected "6nkh" [edit=sysop:move=sysop]

←Older revision

Revision as of 10:41, 16 January 2019

OCA: New page: '''Unreleased structure''' The entry 6nkh is ON HOLD Authors: Dan, Q., Newmister, S.A., Smith, J.L., Sherman, D.H. Description: Structure of MalC Reductase/Diels-Alderase from Malbranc...

OCA — Wed, 16 Jan 2019 10:41:46 GMT

New page: '''Unreleased structure''' The entry 6nkh is ON HOLD Authors: Dan, Q., Newmister, S.A., Smith, J.L., Sherman, D.H. Description: Structure of MalC Reductase/Diels-Alderase from Malbranc...

New page

'''Unreleased structure'''

The entry 6nkh is ON HOLD

Authors: Dan, Q., Newmister, S.A., Smith, J.L., Sherman, D.H.

Description: Structure of MalC Reductase/Diels-Alderase from Malbranchea aurantiaca
[[Category: Unreleased Structures]]
[[Category: Newmister, S.A]]
[[Category: Smith, J.L]]
[[Category: Sherman, D.H]]
[[Category: Dan, Q]]