6nkk - Revision history

OCA at 14:48, 13 March 2024

OCA — Wed, 13 Mar 2024 14:48:07 GMT

←Older revision		Revision as of 14:48, 13 March 2024
Line 3:		Line 3:
	<StructureSection load='6nkk' size='340' side='right'caption='[[6nkk]], [[Resolution\|resolution]] 2.30Å' scene=''>		<StructureSection load='6nkk' size='340' side='right'caption='[[6nkk]], [[Resolution\|resolution]] 2.30Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[6nkk]] is a 6 chain structure with sequence from [~~http~~://en.wikipedia.org/wiki/~~Nrrl_746 Nrrl 746~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6NKK OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=6NKK FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6nkk]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Penicillium_fellutanum Penicillium fellutanum]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6NKK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6NKK FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene>, <scene name='pdbligand=PM7:(5aS,12aS,13aS)-12,12-dimethyl-2,3,11,12,12a,13-hexahydro-1H,5H,6H-5a,13a-(epiminomethano)indolizino[7,6-b]carbazol-14-one'>PM7</scene>~~</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]] 2.299Å</td></tr>
-	~~<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[6nkh\|6nkh]]</td></tr>~~	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene>, <scene name='pdbligand=PM7:(5aS,12aS,13aS)-12,12-dimethyl-2,3,11,12,12a,13-hexahydro-1H,5H,6H-5a,13a-(epiminomethano)indolizino[7,6-b]carbazol-14-one'>PM7</scene></td></tr>
-	~~<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">phqE ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=70095 NRRL 746])~~</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=6nkk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6nkk OCA], [https://pdbe.org/6nkk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6nkk RCSB], [https://www.ebi.ac.uk/pdbsum/6nkk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6nkk ProSAT]</span></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=6nkk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6nkk OCA], [~~http~~://pdbe.org/6nkk PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=6nkk RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/6nkk PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=6nkk ProSAT]</span></td></tr>	+
	</table>		</table>
-	~~<div style~~=~~"background-color:#fffaf0;">~~	+	== Function ==
-	=~~= Publication Abstract from PubMed~~ ==	+	[https://www.uniprot.org/uniprot/PHQE_PENFE PHQE_PENFE] Short-chain dehydrogenase/reductase; part of the gene cluster that mediates the biosynthesis of paraherquamide, a fungal indole alkaloid that belongs to a family of natural products containing a characteristic bicyclo[2.2.2]diazaoctane core (PubMed:23213353). The first steps in the biosynthesis of paraherquamide is the production of the beta-methyl-proline precursor from L-isoleucine (Probable). They require oxidation of a terminally hydroxylated L-isoleucine to the corresponding aldehyde by enzymes which have still to be identified (Probable). Spontaneous cyclization and dehydration would yield the 4-methyl pyrolline-5-carboxylic acid, which is then reduced by the pyrroline-5-carboxylate reductase phqD leading to the beta-methyl-proline precursor (Probable). The next step of paraherquamide biosynthesis involves coupling of beta-methyl-proline and L-tryptophan by the bimodular NRPS phqB, to produce a monooxopiperazine intermediate (Probable). The reductase (R) domain of phqB utilizes NADPH for hydride transfer to reduce the thioester bond of the T domain-tethered linear dipeptide to a hemithioaminal intermediate, which spontaneously cleaves the C-S bond to release the aldehyde product (PubMed:31548667). This compound undergoes spontaneous cyclization and dehydration to give a dienamine which is reverse prenylated at C-2 by the reverse prenyltransferase phqJ (Probable). The other prenyltransferase present in the cluster, phqI may be a redundant gene in the pathway (Probable). During biosynthetic assembly, the key step to produce the polycyclic core is catalyzed by the bifunctional reductase and intramolecular [4+2] Diels-Alderase, phqE, resulting in formation of the [2.2.2] diazaoctane intermediate preparaherquamide (PubMed:31548667). Following formation of preparaherquamide, an indole 2,3-epoxidation-initiated pinacol-like rearrangement is catalyzed by the phqK FAD-dependent monooxygenase (Probable). The prenyltransferase phqA, the cytochrome P450 monooxygenase phqL, and the FAD-linked oxidoreductase phqH (or the cytochrome P450 monooxygenase phqM), are proposed to be involved in the formation of the pyran ring (Probable). The FAD-dependent monooxygenase phqK is likely responsible for generation of the spiro-oxindole, and the N-methylation is likely mediated by the phqN methyltransferase leading to the isolable natural product paraherquamide F (Probable). However, the order of these biosynthetic steps has still to be determined (Probable). In late-stage paraherquamide biosynthesis, the third P450 monooxygenase, phqO, is probably responsible for the C-14 hydroxylation, transforming paraherquamide F to paraherquamide G, and paraherquamide E to the final product paraherquamide A (Probable). The expansion from the 6-membered ring pyran (in paraherquamides F and G) to the 7-membered dioxepin ring (in paraherquamides A and E) represents a poorly understood but intriguing process that probably involves the 2-oxoglutarate-dependent dioxygenase phqC (Probable). Finally, the remaining members of the paraherquamide cluster, including phqI as well as phqM (or phqH), do not have a clearly prescribed role and appear to be redundant (Probable).<ref>PMID:23213353</ref> <ref>PMID:31548667</ref> <ref>PMID:23213353</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 6nkk" style="background-color~~:~~#fffaf0;">~~</~~div~~>	+
	== References ==		== References ==
	<references/>		<references/>
Line 23:		Line 15:
	</StructureSection>		</StructureSection>
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: ~~Nrrl 746~~]]	+	[[Category: Penicillium fellutanum]]
-	[[Category: Dan, Q]]	+	[[Category: Dan Q]]
-	[[Category: Newmister~~, S A~~]]	+	[[Category: Newmister SA]]
-	[[Category: Sherman~~, D H~~]]	+	[[Category: Sherman DH]]
-	[[Category: Smith~~, J L]]~~	+	[[Category: Smith JL]]
-	~~[[Category: Diels-alderase]]~~	+
-	~~[[Category: Oxidoreductase]]~~	+
-	~~[[Category: Reductase~~]]	+

OCA at 08:27, 6 November 2019

OCA — Wed, 06 Nov 2019 08:27:13 GMT

←Older revision		Revision as of 08:27, 6 November 2019
Line 3:		Line 3:
	<StructureSection load='6nkk' size='340' side='right'caption='[[6nkk]], [[Resolution\|resolution]] 2.30Å' scene=''>		<StructureSection load='6nkk' size='340' side='right'caption='[[6nkk]], [[Resolution\|resolution]] 2.30Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[6nkk]] is a 6 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6NKK OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6NKK FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6nkk]] is a 6 chain structure with sequence from [http://en.wikipedia.org/wiki/Nrrl_746 Nrrl 746]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6NKK OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6NKK FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene>, <scene name='pdbligand=PM7:(5aS,12aS,13aS)-12,12-dimethyl-2,3,11,12,12a,13-hexahydro-1H,5H,6H-5a,13a-(epiminomethano)indolizino[7,6-b]carbazol-14-one'>PM7</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene>, <scene name='pdbligand=PM7:(5aS,12aS,13aS)-12,12-dimethyl-2,3,11,12,12a,13-hexahydro-1H,5H,6H-5a,13a-(epiminomethano)indolizino[7,6-b]carbazol-14-one'>PM7</scene></td></tr>
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[6nkh\|6nkh]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[6nkh\|6nkh]]</td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">phqE ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=70095 NRRL 746])</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=6nkk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6nkk OCA], [http://pdbe.org/6nkk PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6nkk RCSB], [http://www.ebi.ac.uk/pdbsum/6nkk PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6nkk ProSAT]</span></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=6nkk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6nkk OCA], [http://pdbe.org/6nkk PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6nkk RCSB], [http://www.ebi.ac.uk/pdbsum/6nkk PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6nkk ProSAT]</span></td></tr>
	</table>		</table>
Line 22:		Line 23:
	</StructureSection>		</StructureSection>
	[[Category: Large Structures]]		[[Category: Large Structures]]
		+	[[Category: Nrrl 746]]
	[[Category: Dan, Q]]		[[Category: Dan, Q]]
	[[Category: Newmister, S A]]		[[Category: Newmister, S A]]

OCA at 05:20, 10 October 2019

OCA — Thu, 10 Oct 2019 05:20:45 GMT

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

-	~~The entry~~ 6nkk is ~~ON HOLD until Paper~~ Publication	+	==Structure of PhqE Reductase/Diels-Alderase from Penicillium fellutanum in complex with NADP+ and premalbrancheamide==
		+	<StructureSection load='6nkk' size='340' side='right'caption='[[6nkk]], [[Resolution\|resolution]] 2.30Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[6nkk]] is a 6 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6NKK OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6NKK FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene>, <scene name='pdbligand=PM7:(5aS,12aS,13aS)-12,12-dimethyl-2,3,11,12,12a,13-hexahydro-1H,5H,6H-5a,13a-(epiminomethano)indolizino[7,6-b]carbazol-14-one'>PM7</scene></td></tr>
		+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[6nkh\|6nkh]]</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=6nkk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6nkk OCA], [http://pdbe.org/6nkk PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6nkk RCSB], [http://www.ebi.ac.uk/pdbsum/6nkk PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6nkk 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: Newmister, S.A~~., Dan, Q., ~~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 PhqE Reductase~~/~~Diels-Alderase from Penicillium fellutanum in complex with NADP+ and premalbrancheamide~~	+	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 6nkk" 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 07:44, 10 May 2019

OCA — Fri, 10 May 2019 07:44:21 GMT

←Older revision		Revision as of 07:44, 10 May 2019
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

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

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

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

OCA — Wed, 16 Jan 2019 10:42:06 GMT

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

←Older revision

Revision as of 10:42, 16 January 2019

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

OCA — Wed, 16 Jan 2019 10:42:04 GMT

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

New page

'''Unreleased structure'''

The entry 6nkk is ON HOLD

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

Description: Structure of PhqE Reductase/Diels-Alderase from Penicillium fellutanum in complex with NADP+ and premalbrancheamide
[[Category: Unreleased Structures]]
[[Category: Newmister, S.A]]
[[Category: Smith, J.L]]
[[Category: Sherman, D.H]]
[[Category: Dan, Q]]