PIKA3_STRVZ
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 03-AUG-2022, entry version 119.
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; Actinobacteria; Streptomycetales; Streptomycetaceae;
OC 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}.
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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 SMR; Q9ZGI3; -.
DR DIP; DIP-61040N; -.
DR KEGG; ag:AAC69331; -.
DR PATRIC; fig|54571.11.peg.3231; -.
DR BioCyc; MetaCyc:MON-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 Gene3D; 1.10.1200.10; -; 1.
DR Gene3D; 3.40.366.10; -; 1.
DR Gene3D; 3.40.47.10; -; 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 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; SM00825; PKS_KS; 1.
DR SMART; SM00823; PKS_PP; 1.
DR SUPFAM; SSF101173; SSF101173; 1.
DR SUPFAM; SSF47336; SSF47336; 1.
DR SUPFAM; SSF51735; SSF51735; 2.
DR SUPFAM; SSF52151; SSF52151; 1.
DR SUPFAM; SSF53901; SSF53901; 1.
DR SUPFAM; SSF55048; SSF55048; 1.
DR PROSITE; PS00606; B_KETOACYL_SYNTHASE; 1.
DR PROSITE; PS50075; CARRIER; 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 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 37..467
FT /note="Beta-ketoacyl synthase"
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:PRU10022,
FT ECO:0000305|PubMed:24965656"
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 10-
FT deoxymethynolide macrolactone."
FT /evidence="ECO:0000269|PubMed:24965656"
FT MUTAGEN 747
FT /note="R->A: Exhibits 5-fold reduced formation of the 10-
FT deoxymethynolide macrolactone."
FT /evidence="ECO:0000269|PubMed:24965656"
FT MUTAGEN 766
FT /note="E->R: Exhibits a reduced formation of the 10-
FT deoxymethynolide macrolactone."
FT /evidence="ECO:0000269|PubMed:24965656"
FT MUTAGEN 768
FT /note="E->R: Exhibits a reduced formation of the 10-
FT deoxymethynolide macrolactone."
FT /evidence="ECO:0000269|PubMed:24965656"
FT MUTAGEN 1133
FT /note="R->E: Exhibits 14-fold reduced formation of the 10-
FT deoxymethynolide macrolactone."
FT /evidence="ECO:0000269|PubMed:24965656"
FT MUTAGEN 1137
FT /note="H->E: Exhibits 2-fold reduced formation of the 10-
FT deoxymethynolide macrolactone."
FT /evidence="ECO:0000269|PubMed:24965656"
FT MUTAGEN 1308
FT /note="R->E: Exhibits 8-fold reduced formation of the 10-
FT 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
