ID PIKA3_STRVZ Reviewed; 1562 AA. AC Q9ZGI3; DT 08-JUN-2016, integrated into UniProtKB/Swiss-Prot. DT 01-MAY-1999, sequence version 1. DT 27-MAR-2024, entry version 126. DE RecName: Full=Narbonolide/10-deoxymethynolide synthase PikA3, module 5 {ECO:0000305}; DE EC=2.3.1.239 {ECO:0000269|PubMed:10421766, ECO:0000305|PubMed:24965656}; DE EC=2.3.1.240 {ECO:0000269|PubMed:10421766, ECO:0000305|PubMed:24965656}; DE AltName: Full=Narbonolide/10-deoxymethynolide synthase PikAIII {ECO:0000305}; DE AltName: Full=Pikromycin polyketide synthase component PikAIII {ECO:0000303|PubMed:10421766}; DE Short=Pikromycin PKS component PikAIII {ECO:0000303|PubMed:10421766}; DE AltName: Full=Type I modular polyketide synthase PikAIII {ECO:0000303|PubMed:10421766}; DE Short=PKS {ECO:0000303|PubMed:10421766}; GN Name=pikAIII {ECO:0000303|PubMed:9770448}; GN ORFNames=BN2537_6637 {ECO:0000312|EMBL:CUM38836.1}; OS Streptomyces venezuelae. OC Bacteria; Actinomycetota; Actinomycetes; Kitasatosporales; OC Streptomycetaceae; Streptomyces. OX NCBI_TaxID=54571; RN [1] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND PATHWAY. RC STRAIN=ATCC 15439 / DSM 41110 / IMRU3627 / M-2140; RX PubMed=9770448; DOI=10.1073/pnas.95.21.12111; RA Xue Y., Zhao L., Liu H.W., Sherman D.H.; RT "A gene cluster for macrolide antibiotic biosynthesis in Streptomyces RT venezuelae: architecture of metabolic diversity."; RL Proc. Natl. Acad. Sci. U.S.A. 95:12111-12116(1998). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RC STRAIN=ATCC 15439 / DSM 41110 / IMRU3627 / M-2140; RA Babu N.S., Beckwith C.J., Beseler K.G., Brison A., Carone J.V., RA Caskin T.P., Diamond M., Durham M.E., Foxe J.M., Go M., Henderson B.A., RA Jones I.B., McGettigan J.A., Micheletti S.J., Nasrallah M.E., Ortiz D., RA Piller C.R., Privatt S.R., Schneider S.L., Sharp S., Smith T.C., RA Stanton J.D., Ullery H.E., Wilson R.J., Serrano M.G., Buck G., Lee V., RA Wang Y., Carvalho R., Voegtly L., Shi R., Duckworth R., Johnson A., RA Loviza R., Walstead R., Shah Z., Kiflezghi M., Wade K., Ball S.L., RA Bradley K.W., Asai D.J., Bowman C.A., Russell D.A., Pope W.H., RA Jacobs-Sera D., Hendrix R.W., Hatfull G.F.; RL Submitted (AUG-2015) to the EMBL/GenBank/DDBJ databases. RN [3] RP FUNCTION, AND CATALYTIC ACTIVITY. RX PubMed=10421766; DOI=10.1016/s1074-5521(99)80087-8; RA Tang L., Fu H., Betlach M.C., McDaniel R.; RT "Elucidating the mechanism of chain termination switching in the RT picromycin/methymycin polyketide synthase."; RL Chem. Biol. 6:553-558(1999). RN [4] RP FUNCTION, PATHWAY, AND SUBUNIT. RX PubMed=19027305; DOI=10.1016/j.bmc.2008.10.082; RA Kittendorf J.D., Sherman D.H.; RT "The methymycin/pikromycin pathway: a model for metabolic diversity in RT natural product biosynthesis."; RL Bioorg. Med. Chem. 17:2137-2146(2009). RN [5] RP FUNCTION, CATALYTIC ACTIVITY, MUTAGENESIS OF GLU-735; ARG-747; GLU-766; RP GLU-768; ARG-1133; HIS-1137 AND ARG-1308, ACTIVE SITE, COFACTOR, REACTION RP MECHANISM, AND PHOSPHOPANTETHEINYLATION AT SER-1438. RX PubMed=24965656; DOI=10.1038/nature13409; RA Whicher J.R., Dutta S., Hansen D.A., Hale W.A., Chemler J.A., Dosey A.M., RA Narayan A.R., Haakansson K., Sherman D.H., Smith J.L., Skiniotis G.; RT "Structural rearrangements of a polyketide synthase module during its RT catalytic cycle."; RL Nature 510:560-564(2014). RN [6] RP X-RAY CRYSTALLOGRAPHY (1.75 ANGSTROMS) OF 1534-1562, AND SUBUNIT. RX PubMed=19146481; DOI=10.1021/cb8002607; RA Buchholz T.J., Geders T.W., Bartley F.E., Reynolds K.A., Smith J.L., RA Sherman D.H.; RT "Structural basis for binding specificity between subclasses of modular RT polyketide synthase docking domains."; RL ACS Chem. Biol. 4:41-52(2009). CC -!- FUNCTION: Involved in the biosynthesis of 12- and 14-membered ring CC macrolactone antibiotics such as methymycin and neomethymycin, and CC pikromycin and narbomycin, respectively. Component of the pikromycin CC PKS which catalyzes the biosynthesis of both precursors 10- CC deoxymethynolide (12-membered ring macrolactone) and narbonolide (14- CC membered ring macrolactone). Chain elongation through PikAI, PikAII and CC PikAIII followed by thioesterase catalyzed termination results in the CC production of 10-deoxymethynolide, while continued elongation through CC PikAIV, followed by thioesterase (TE) catalyzed cyclization results in CC the biosynthesis of the narbonolide. {ECO:0000269|PubMed:10421766, CC ECO:0000269|PubMed:24965656, ECO:0000305|PubMed:19027305}. CC -!- CATALYTIC ACTIVITY: CC Reaction=5 (S)-methylmalonyl-CoA + 11 H(+) + malonyl-CoA + 5 NADPH = CC 10-deoxymethynolide + 6 CO2 + 6 CoA + 2 H2O + 5 NADP(+); CC Xref=Rhea:RHEA:43056, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, CC ChEBI:CHEBI:16526, ChEBI:CHEBI:29461, ChEBI:CHEBI:57287, CC ChEBI:CHEBI:57327, ChEBI:CHEBI:57384, ChEBI:CHEBI:57783, CC ChEBI:CHEBI:58349; EC=2.3.1.239; CC Evidence={ECO:0000269|PubMed:10421766, ECO:0000305|PubMed:24965656}; CC -!- CATALYTIC ACTIVITY: CC Reaction=6 (S)-methylmalonyl-CoA + 12 H(+) + malonyl-CoA + 5 NADPH = 7 CC CO2 + 7 CoA + 2 H2O + 5 NADP(+) + narbonolide; Xref=Rhea:RHEA:42844, CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:16526, CC ChEBI:CHEBI:29650, ChEBI:CHEBI:57287, ChEBI:CHEBI:57327, CC ChEBI:CHEBI:57384, ChEBI:CHEBI:57783, ChEBI:CHEBI:58349; CC EC=2.3.1.240; Evidence={ECO:0000269|PubMed:10421766, CC ECO:0000305|PubMed:24965656}; CC -!- COFACTOR: CC Name=pantetheine 4'-phosphate; Xref=ChEBI:CHEBI:47942; CC Evidence={ECO:0000305|PubMed:24965656}; CC Note=Binds 1 phosphopantetheine covalently. {ECO:0000305}; CC -!- PATHWAY: Antibiotic biosynthesis. {ECO:0000305|PubMed:19027305, CC ECO:0000305|PubMed:9770448}. CC -!- SUBUNIT: Homodimer (PubMed:19146481). Pikromycin PKS consists of a CC combination of multimodular (PikAI and PikAII) and monomodular (PikAIII CC and PikAIV) polypeptides each coding for a functional synthase subunit CC which participates in 1 (monomodular) or 2 (multimodular) of the six CC FAS-like elongation steps required for formation of the polyketide. CC Module 1, 2, 3, 4, 5, and 6 participating in biosynthesis steps 1, 2, CC 3, 4, 5, and 6, respectively. {ECO:0000269|PubMed:19146481, CC ECO:0000305|PubMed:19027305}. CC -!- INTERACTION: CC Q9ZGI3; Q9ZGI3: pikAIII; NbExp=3; IntAct=EBI-9023465, EBI-9023465; CC -!- MISCELLANEOUS: Type I modular polyketide synthases (PKSs) catalyze the CC step-wise condensation of simple carboxylic acid derivatives. CC Organizationally, type I PKSs are arranged into modules, wherein each CC module is comprised of a set of catalytic activities that is CC responsible for a single elongation of the polyketide chain and the CC appropriate reductive processing of the beta-keto functionality. A CC minimal elongation module contains an acyl transferase (AT) domain, an CC acyl-carrier protein (ACP) domain, and a ketosynthase (KS) domain. The CC AT domain is responsible for loading the methylmalonyl-CoA extender CC unit onto the phosphopantetheinylated ACP domain. Subsequently, the KS CC domain decarboxylates and then condenses the ACP-bound extender unit CC with the growing polyketide chain obtained from the preceding module to CC yield an ACP-bound beta-ketoacyl intermediate. In addition to the three CC core domains, each elongation module may contain up to three additional CC domains: a ketoreductase (KR), dehydratase (DH), and an enoyl reductase CC (ER) that are responsible for the reductive processing of the beta-keto CC functionality prior to the next extension step. The presence of a KR CC domain alone gives rise to a beta-hydroxyl functionality, the presence CC of both a KR and a DH domain generates an alkene, while the combination CC of KR, DH, and ER results in complete reduction to the alkane. Finally, CC a thioesterase (TE) domain, typically found at the terminus of the last CC elongation module, catalyzes the termination of polyketide CC biosynthesis. The activity of this domain results in cleavage of the CC acyl chain from the adjacent ACP and formation of the macrocyclic ring. CC {ECO:0000305|PubMed:19027305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AF079138; AAC69331.1; -; Genomic_DNA. DR EMBL; LN881739; CUM38836.1; -; Genomic_DNA. DR PIR; T17411; T17411. DR PDB; 3F5H; X-ray; 1.75 A; A/B=1534-1562. DR PDBsum; 3F5H; -. DR AlphaFoldDB; Q9ZGI3; -. DR EMDB; EMD-5647; -. DR EMDB; EMD-5648; -. DR EMDB; EMD-5649; -. DR EMDB; EMD-5651; -. DR EMDB; EMD-5653; -. DR EMDB; EMD-5662; -. DR EMDB; EMD-5663; -. DR EMDB; EMD-5664; -. DR EMDB; EMD-5665; -. DR EMDB; EMD-5666; -. DR EMDB; EMD-5667; -. DR SMR; Q9ZGI3; -. DR DIP; DIP-61040N; -. DR KEGG; ag:AAC69331; -. DR PATRIC; fig|54571.11.peg.3231; -. DR BioCyc; MetaCyc:MONOMER-18413; -. DR BRENDA; 2.3.1.239; 6106. DR BRENDA; 2.3.1.240; 6106. DR EvolutionaryTrace; Q9ZGI3; -. DR GO; GO:0004315; F:3-oxoacyl-[acyl-carrier-protein] synthase activity; IEA:InterPro. DR GO; GO:0016747; F:acyltransferase activity, transferring groups other than amino-acyl groups; IDA:UniProtKB. DR GO; GO:0042802; F:identical protein binding; IPI:IntAct. DR GO; GO:0031177; F:phosphopantetheine binding; TAS:UniProtKB. DR GO; GO:0006633; P:fatty acid biosynthetic process; IEA:InterPro. DR GO; GO:0033068; P:macrolide biosynthetic process; IDA:UniProtKB. DR CDD; cd08952; KR_1_SDR_x; 1. DR CDD; cd00833; PKS; 1. DR Gene3D; 3.30.70.3290; -; 1. DR Gene3D; 3.40.47.10; -; 1. DR Gene3D; 6.10.40.10; -; 1. DR Gene3D; 1.10.1200.10; ACP-like; 1. DR Gene3D; 3.40.366.10; Malonyl-Coenzyme A Acyl Carrier Protein, domain 2; 1. DR Gene3D; 3.40.50.720; NAD(P)-binding Rossmann-like Domain; 1. DR InterPro; IPR001227; Ac_transferase_dom_sf. DR InterPro; IPR036736; ACP-like_sf. DR InterPro; IPR014043; Acyl_transferase. DR InterPro; IPR016035; Acyl_Trfase/lysoPLipase. DR InterPro; IPR018201; Ketoacyl_synth_AS. DR InterPro; IPR014031; Ketoacyl_synth_C. DR InterPro; IPR014030; Ketoacyl_synth_N. DR InterPro; IPR016036; Malonyl_transacylase_ACP-bd. DR InterPro; IPR036291; NAD(P)-bd_dom_sf. DR InterPro; IPR032821; PKS_assoc. DR InterPro; IPR020841; PKS_Beta-ketoAc_synthase_dom. DR InterPro; IPR013968; PKS_KR. DR InterPro; IPR020806; PKS_PP-bd. DR InterPro; IPR015083; Polyketide_synth_docking. DR InterPro; IPR036299; Polyketide_synth_docking_sf. DR InterPro; IPR009081; PP-bd_ACP. DR InterPro; IPR006162; Ppantetheine_attach_site. DR InterPro; IPR016039; Thiolase-like. DR PANTHER; PTHR43775; FATTY ACID SYNTHASE; 1. DR PANTHER; PTHR43775:SF51; PHENOLPHTHIOCEROL_PHTHIOCEROL POLYKETIDE SYNTHASE SUBUNIT E; 1. DR Pfam; PF00698; Acyl_transf_1; 1. DR Pfam; PF08990; Docking; 1. DR Pfam; PF16197; KAsynt_C_assoc; 1. DR Pfam; PF00109; ketoacyl-synt; 1. DR Pfam; PF02801; Ketoacyl-synt_C; 1. DR Pfam; PF08659; KR; 1. DR Pfam; PF00550; PP-binding; 1. DR SMART; SM00827; PKS_AT; 1. DR SMART; SM00822; PKS_KR; 1. DR SMART; SM00825; PKS_KS; 1. DR SMART; SM00823; PKS_PP; 1. DR SMART; SM01294; PKS_PP_betabranch; 1. DR SUPFAM; SSF47336; ACP-like; 1. DR SUPFAM; SSF101173; Docking domain B of the erythromycin polyketide synthase (DEBS); 1. DR SUPFAM; SSF52151; FabD/lysophospholipase-like; 1. DR SUPFAM; SSF51735; NAD(P)-binding Rossmann-fold domains; 2. DR SUPFAM; SSF55048; Probable ACP-binding domain of malonyl-CoA ACP transacylase; 1. DR SUPFAM; SSF53901; Thiolase-like; 1. DR PROSITE; PS50075; CARRIER; 1. DR PROSITE; PS00606; KS3_1; 1. DR PROSITE; PS52004; KS3_2; 1. DR PROSITE; PS00012; PHOSPHOPANTETHEINE; 1. PE 1: Evidence at protein level; KW 3D-structure; Acyltransferase; Antibiotic biosynthesis; KW Multifunctional enzyme; NADP; Phosphopantetheine; Phosphoprotein; KW Transferase. FT CHAIN 1..1562 FT /note="Narbonolide/10-deoxymethynolide synthase PikA3, FT module 5" FT /id="PRO_0000436359" FT DOMAIN 34..464 FT /note="Ketosynthase family 3 (KS3)" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01348" FT DOMAIN 1403..1478 FT /note="Carrier" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258" FT REGION 37..1475 FT /note="Module 5" FT /evidence="ECO:0000305" FT REGION 565..866 FT /note="Acyltransferase" FT /evidence="ECO:0000305" FT REGION 1116..1293 FT /note="Beta-ketoacyl reductase" FT /evidence="ECO:0000305" FT REGION 1519..1548 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT ACT_SITE 209 FT /note="Acyl-thioester intermediate; for beta-ketoacyl FT synthase activity" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01348, FT ECO:0000305|PubMed:24965656" FT ACT_SITE 344 FT /note="For beta-ketoacyl synthase activity" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01348" FT ACT_SITE 384 FT /note="For beta-ketoacyl synthase activity" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01348" FT ACT_SITE 655 FT /note="Acyl-ester intermediate; for acyltransferase FT activity" FT /evidence="ECO:0000250|UniProtKB:Q03133" FT ACT_SITE 1263 FT /note="Acyl-ester intermediate; for beta-ketoacyl reductase FT activity" FT /evidence="ECO:0000250|UniProtKB:Q03132, FT ECO:0000250|UniProtKB:Q9ZGI4" FT BINDING 1124..1127 FT /ligand="NADP(+)" FT /ligand_id="ChEBI:CHEBI:58349" FT /ligand_note="for beta-ketoacyl reductase activity" FT /evidence="ECO:0000250|UniProtKB:Q03131" FT BINDING 1147..1150 FT /ligand="NADP(+)" FT /ligand_id="ChEBI:CHEBI:58349" FT /ligand_note="for beta-ketoacyl reductase activity" FT /evidence="ECO:0000250|UniProtKB:Q03131" FT BINDING 1176..1177 FT /ligand="NADP(+)" FT /ligand_id="ChEBI:CHEBI:58349" FT /ligand_note="for beta-ketoacyl reductase activity" FT /evidence="ECO:0000250|UniProtKB:Q03131" FT BINDING 1226 FT /ligand="NADP(+)" FT /ligand_id="ChEBI:CHEBI:58349" FT /ligand_note="for beta-ketoacyl reductase activity" FT /evidence="ECO:0000250|UniProtKB:Q03131" FT BINDING 1248..1249 FT /ligand="NADP(+)" FT /ligand_id="ChEBI:CHEBI:58349" FT /ligand_note="for beta-ketoacyl reductase activity" FT /evidence="ECO:0000250|UniProtKB:Q03131" FT MOD_RES 1438 FT /note="O-(pantetheine 4'-phosphoryl)serine" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258, FT ECO:0000305|PubMed:24965656" FT MUTAGEN 735 FT /note="E->A: Exhibits 10-fold reduced formation of the FT 10-deoxymethynolide macrolactone." FT /evidence="ECO:0000269|PubMed:24965656" FT MUTAGEN 747 FT /note="R->A: Exhibits 5-fold reduced formation of the FT 10-deoxymethynolide macrolactone." FT /evidence="ECO:0000269|PubMed:24965656" FT MUTAGEN 766 FT /note="E->R: Exhibits a reduced formation of the FT 10-deoxymethynolide macrolactone." FT /evidence="ECO:0000269|PubMed:24965656" FT MUTAGEN 768 FT /note="E->R: Exhibits a reduced formation of the FT 10-deoxymethynolide macrolactone." FT /evidence="ECO:0000269|PubMed:24965656" FT MUTAGEN 1133 FT /note="R->E: Exhibits 14-fold reduced formation of the FT 10-deoxymethynolide macrolactone." FT /evidence="ECO:0000269|PubMed:24965656" FT MUTAGEN 1137 FT /note="H->E: Exhibits 2-fold reduced formation of the FT 10-deoxymethynolide macrolactone." FT /evidence="ECO:0000269|PubMed:24965656" FT MUTAGEN 1308 FT /note="R->E: Exhibits 8-fold reduced formation of the FT 10-deoxymethynolide macrolactone." FT /evidence="ECO:0000269|PubMed:24965656" FT HELIX 1544..1546 FT /evidence="ECO:0007829|PDB:3F5H" FT HELIX 1549..1557 FT /evidence="ECO:0007829|PDB:3F5H" FT HELIX 1559..1562 FT /evidence="ECO:0007829|PDB:3F5H" SQ SEQUENCE 1562 AA; 163594 MW; DB4BA0DAAA15B63F CRC64; MANNEDKLRD YLKRVTAELQ QNTRRLREIE GRTHEPVAIV GMACRLPGGV ASPEDLWQLV AGDGDAISEF PQDRGWDVEG LYDPDPDASG RTYCRSGGFL HDAGEFDADF FGISPREALA MDPQQRLSLT TAWEAIESAG IDPTALKGSG LGVFVGGWHT GYTSGQTTAV QSPELEGHLV SGAALGFLSG RIAYVLGTDG PALTVDTACS SSLVALHLAV QALRKGECDM ALAGGVTVMP NADLFVQFSR QRGLAADGRS KAFATSADGF GPAEGAGVLL VERLSDARRN GHRILAVVRG SAVNQDGASN GLTAPHGPSQ QRVIRRALAD ARLAPGDVDV VEAHGTGTRL GDPIEAQALI ATYGQEKSSE QPLRLGALKS NIGHTQAAAG VAGVIKMVQA MRHGLLPKTL HVDEPSDQID WSAGTVELLT EAVDWPEKQD GGLRRAAVSS FGISGTNAHV VLEEAPAVED SPAVEPPAGG GVVPWPVSAK TPAALDAQIG QLAAYADGRT DVDPAVAARA LVDSRTAMEH RAVAVGDSRE ALRDALRMPE GLVRGTSSDV GRVAFVFPGQ GTQWAGMGAE LLDSSPEFAA SMAECETALS RYVDWSLEAV VRQEPGAPTL DRVDVVQPVT FAVMVSLAKV WQHHGITPQA VVGHSQGEIA AAYVAGALTL DDAARVVTLR SKSIAAHLAG KGGMISLALD EAAVLKRLSD FDGLSVAAVN GPTATVVSGD PTQIEELART CEADGVRARI IPVDYASHSR QVEIIEKELA EVLAGLAPQA PHVPFFSTLE GTWITEPVLD GTYWYRNLRH RVGFAPAVET LAVDGFTHFI EVSAHPVLTM TLPETVTGLG TLRREQGGQE RLVTSLAEAW ANGLTIDWAP ILPTATGHHP ELPTYAFQTE RFWLQSSAPT SAADDWRYRV EWKPLTASGQ ADLSGRWIVA VGSEPEAELL GALKAAGAEV DVLEAGADDD REALAARLTA LTTGDGFTGV VSLLDDLVPQ VAWVQALGDA GIKAPLWSVT QGAVSVGRLD TPADPDRAML WGLGRVVALE HPERWAGLVD LPAQPDAAAL AHLVTALSGA TGEDQIAIRT TGLHARRLAR APLHGRRPTR DWQPHGTVLI TGGTGALGSH AARWMAHHGA EHLLLVSRSG EQAPGATQLT AELTASGARV TIAACDVADP HAMRTLLDAI PAETPLTAVV HTAGAPGGDP LDVTGPEDIA RILGAKTSGA EVLDDLLRGT PLDAFVLYSS NAGVWGSGSQ GVYAAANAHL DALAARRRAR GETATSVAWG LWAGDGMGRG ADDAYWQRRG IRPMSPDRAL DELAKALSHD ETFVAVADVD WERFAPAFTV SRPSLLLDGV PEARQALAAP VGAPAPGDAA VAPTGQSSAL AAITALPEPE RRPALLTLVR THAAAVLGHS SPDRVAPGRA FTELGFDSLT AVQLRNQLST VVGNRLPATT VFDHPTPAAL AAHLHEAYLA PAEPAPTDWE GRVRRALAEL PLDRLRDAGV LDTVLRLTGI EPEPGSGGSD GGAADPGAEP EASIDDLDAE ALIRMALGPR NT //