ACVA_ACRCH
ID ACVA_ACRCH Reviewed; 3712 AA.
AC P25464;
DT 01-MAY-1992, integrated into UniProtKB/Swiss-Prot.
DT 01-MAY-1992, sequence version 1.
DT 03-AUG-2022, entry version 111.
DE RecName: Full=N-(5-amino-5-carboxypentanoyl)-L-cysteinyl-D-valine synthase {ECO:0000250|UniProtKB:P19787};
DE EC=6.3.2.26 {ECO:0000250|UniProtKB:P19787};
DE AltName: Full=Delta-(L-alpha-aminoadipyl)-L-cysteinyl-D-valine synthetase {ECO:0000303|PubMed:2076552};
DE Short=ACV synthetase {ECO:0000303|PubMed:2076552};
DE Short=ACVS {ECO:0000303|PubMed:2076552};
GN Name=PCBAB {ECO:0000303|PubMed:2076552};
OS Acremonium chrysogenum (Cephalosporium acremonium).
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Sordariomycetes;
OC Hypocreomycetidae; Hypocreales; Hypocreales incertae sedis; Acremonium.
OX NCBI_TaxID=5044;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND FUNCTION.
RX PubMed=1706706; DOI=10.1128/jb.173.7.2354-2365.1991;
RA Gutierrez S., Diez B., Montenegro E., Martin J.F.;
RT "Characterization of the Cephalosporium acremonium pcbAB gene encoding
RT alpha-aminoadipyl-cysteinyl-valine synthetase, a large multidomain peptide
RT synthetase: linkage to the pcbC gene as a cluster of early cephalosporin
RT biosynthetic genes and evidence of multiple functional domains.";
RL J. Bacteriol. 173:2354-2365(1991).
RN [2]
RP PARTIAL NUCLEOTIDE SEQUENCE, PARTIAL PROTEIN SEQUENCE, FUNCTION, DISRUPTION
RP PHENOTYPE, AND PATHWAY.
RC STRAIN=ATCC 11550 / CBS 779.69 / DSM 880 / IMI 49137;
RX PubMed=2076552; DOI=10.1007/bf00327023;
RA Hoskins J.A., O'Callaghan N., Queener S.W., Cantwell C.A., Wood J.S.,
RA Chen V.J., Skatrud P.L.;
RT "Gene disruption of the pcbAB gene encoding ACV synthetase in
RT Cephalosporium acremonium.";
RL Curr. Genet. 18:523-530(1990).
RN [3]
RP FUNCTION, CATALYTIC ACTIVITY, AND PATHWAY.
RX PubMed=9305735; DOI=10.1016/s0014-5793(97)00977-0;
RA Kallow W., Neuhof T., Arezi B., Jungblut P., von Doehren H.;
RT "Penicillin biosynthesis: intermediates of biosynthesis of delta-L-alpha-
RT aminoadipyl-L-cysteinyl-D-valine formed by ACV synthetase from Acremonium
RT chrysogenum.";
RL FEBS Lett. 414:74-78(1997).
CC -!- FUNCTION: Nonribosomal peptide synthetase; part of the gene cluster
CC that mediates the biosynthesis of penicillin, the world's most
CC important antibiotic (PubMed:1706706, PubMed:2076552, PubMed:9305735).
CC The trimodular NRPS PCBAB produces the tripeptide N-[(5S)-5-amino-5-
CC carboxypentanoyl]-L-cysteinyl-D-valine (LLD-ACV or ACV) via
CC condensation of the 3 residues L-2-aminoadipate, L-cysteine and L-
CC valine (PubMed:9305735). The precursor amino acids for penicillin
CC biosynthesis are withdrawn from the vacuolar amino acid pool by the
CC MFS-type transporter penV (By similarity). Each of the constituent
CC amino acids of the tripeptide ACV are activated as aminoacyl-adenylates
CC with peptide bonds formed through the participation of amino acid
CC thioester intermediates (PubMed:9305735). The penicillin biosynthesis
CC occurs via 3 enzymatic steps, the first corresponding to the production
CC of the tripeptide N-[(5S)-5-amino-5-carboxypentanoyl]-L-cysteinyl-D-
CC valine (LLD-ACV or ACV) by the NRPS PCBAB. The tripeptide ACV is then
CC cyclized to isopenicillin N (IPN) by the isopenicillin N synthase PCBCC
CC that forms the beta-lactam nucleus. Finally, the alpha-aminoadipyl side
CC chain is exchanged for phenylacetic acid by the isopenicillin N
CC acyltransferase PCBDE to yield penicillin in the peroxisomal matrix (By
CC similarity). {ECO:0000250|UniProtKB:P19787, ECO:0000269|PubMed:1706706,
CC ECO:0000269|PubMed:2076552, ECO:0000269|PubMed:9305735}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=3 ATP + H2O + L-2-aminoadipate + L-cysteine + L-valine = 3 AMP
CC + 3 diphosphate + 3 H(+) + N-[(5S)-5-amino-5-carboxypentanoyl]-L-
CC cysteinyl-D-valine; Xref=Rhea:RHEA:23196, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:33019,
CC ChEBI:CHEBI:35235, ChEBI:CHEBI:57762, ChEBI:CHEBI:58572,
CC ChEBI:CHEBI:58672, ChEBI:CHEBI:456215; EC=6.3.2.26;
CC Evidence={ECO:0000269|PubMed:9305735};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:23197;
CC Evidence={ECO:0000269|PubMed:9305735};
CC -!- COFACTOR:
CC Name=pantetheine 4'-phosphate; Xref=ChEBI:CHEBI:47942;
CC Note=Binds 3 phosphopantetheines covalently. {ECO:0000255};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000250|UniProtKB:P19787};
CC -!- PATHWAY: Antibiotic biosynthesis; penicillin G biosynthesis; penicillin
CC G from L-alpha-aminoadipate and L-cysteine and L-valine: step 1/3.
CC {ECO:0000269|PubMed:2076552, ECO:0000269|PubMed:9305735}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol
CC {ECO:0000250|UniProtKB:P19787}. Vacuole membrane
CC {ECO:0000250|UniProtKB:P19787}; Peripheral membrane protein
CC {ECO:0000250|UniProtKB:P19787}. Note=Loosely attached to the vacuoles.
CC {ECO:0000250|UniProtKB:P19787}.
CC -!- DOMAIN: NRP synthetases are composed of discrete domains (adenylation
CC (A), thiolation (T) or peptidyl carrier protein (PCP) and condensation
CC (C) domains) which when grouped together are referred to as a single
CC module. Each module is responsible for the recognition (via the A
CC domain) and incorporation of a single amino acid into the growing
CC peptide product. Thus, an NRP synthetase is generally composed of one
CC or more modules and can terminate in a thioesterase domain (TE) that
CC releases the newly synthesized peptide from the enzyme. Occasionally,
CC epimerase (E) domains (responsible for L- to D-amino acid conversion)
CC are present within the NRP synthetase. GliP has the following
CC architecture: A-T-C-A-T-C-A-T-E-TE. {ECO:0000250|UniProtKB:P19787}.
CC -!- DISRUPTION PHENOTYPE: Impairs the production of beta-lactam antibiotic.
CC {ECO:0000269|PubMed:2076552}.
CC -!- SIMILARITY: Belongs to the NRP synthetase family. {ECO:0000305}.
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DR PIR; A38531; YGCEVC.
DR SMR; P25464; -.
DR ESTHER; cepac-acvs; Thioesterase.
DR PRIDE; P25464; -.
DR UniPathway; UPA00149; UER00239.
DR GO; GO:0005829; C:cytosol; IEA:UniProtKB-SubCell.
DR GO; GO:0005774; C:vacuolar membrane; ISS:GO_Central.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0050564; F:N-(5-amino-5-carboxypentanoyl)-L-cysteinyl-D-valine synthase activity; ISS:GO_Central.
DR GO; GO:0031177; F:phosphopantetheine binding; IEA:InterPro.
DR GO; GO:0042318; P:penicillin biosynthetic process; ISS:GO_Central.
DR Gene3D; 1.10.1200.10; -; 3.
DR Gene3D; 3.30.300.30; -; 3.
DR Gene3D; 3.30.559.10; -; 3.
DR Gene3D; 3.40.50.1820; -; 1.
DR InterPro; IPR010071; AA_adenyl_domain.
DR InterPro; IPR029058; AB_hydrolase.
DR InterPro; IPR036736; ACP-like_sf.
DR InterPro; IPR025110; AMP-bd_C.
DR InterPro; IPR045851; AMP-bd_C_sf.
DR InterPro; IPR020845; AMP-binding_CS.
DR InterPro; IPR000873; AMP-dep_Synth/Lig.
DR InterPro; IPR023213; CAT-like_dom_sf.
DR InterPro; IPR001242; Condensatn.
DR InterPro; IPR020806; PKS_PP-bd.
DR InterPro; IPR009081; PP-bd_ACP.
DR InterPro; IPR006162; Ppantetheine_attach_site.
DR InterPro; IPR001031; Thioesterase.
DR Pfam; PF00501; AMP-binding; 3.
DR Pfam; PF13193; AMP-binding_C; 2.
DR Pfam; PF00668; Condensation; 3.
DR Pfam; PF00550; PP-binding; 3.
DR Pfam; PF00975; Thioesterase; 1.
DR SMART; SM00823; PKS_PP; 3.
DR SUPFAM; SSF47336; SSF47336; 3.
DR SUPFAM; SSF53474; SSF53474; 1.
DR TIGRFAMs; TIGR01733; AA-adenyl-dom; 3.
DR PROSITE; PS00455; AMP_BINDING; 3.
DR PROSITE; PS50075; CARRIER; 3.
DR PROSITE; PS00012; PHOSPHOPANTETHEINE; 2.
PE 1: Evidence at protein level;
KW Antibiotic biosynthesis; ATP-binding; Cytoplasm; Direct protein sequencing;
KW Ligase; Membrane; Multifunctional enzyme; Nucleotide-binding;
KW Phosphopantetheine; Phosphoprotein; Repeat; Vacuole.
FT CHAIN 1..3712
FT /note="N-(5-amino-5-carboxypentanoyl)-L-cysteinyl-D-valine
FT synthase"
FT /id="PRO_0000193058"
FT DOMAIN 790..867
FT /note="Carrier 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT DOMAIN 1879..1956
FT /note="Carrier 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT DOMAIN 2955..3030
FT /note="Carrier 3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT REGION 267..681
FT /note="Adenylation (A) domain 1"
FT /evidence="ECO:0000250|UniProtKB:P19787, ECO:0000255"
FT REGION 895..1348
FT /note="Condensation (C) domain 1"
FT /evidence="ECO:0000250|UniProtKB:P19787, ECO:0000255"
FT REGION 1367..1777
FT /note="Adenylation (A) domain 2"
FT /evidence="ECO:0000250|UniProtKB:P19787, ECO:0000255"
FT REGION 1971..2405
FT /note="Condensation (C) domain 2"
FT /evidence="ECO:0000250|UniProtKB:P19787, ECO:0000255"
FT REGION 2445..2847
FT /note="Adenylation (A) domain 3"
FT /evidence="ECO:0000250|UniProtKB:P19787, ECO:0000255"
FT REGION 3052..3469
FT /note="Epimerase (E) domain"
FT /evidence="ECO:0000250|UniProtKB:P19787, ECO:0000255"
FT REGION 3499..3700
FT /note="Thioesterase (TE) domain"
FT /evidence="ECO:0000250|UniProtKB:P19787, ECO:0000255"
FT MOD_RES 827
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT MOD_RES 1916
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT MOD_RES 2990
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
SQ SEQUENCE 3712 AA; 414775 MW; 4EE3C1EB5EBEF9B7 CRC64;
MALEQWKTTV QSVSERCDLS GLSQHPTDYQ LASTGVKGAG GSSIEERSAI VSDELFSSLR
DVCSQRQLDP RSLMLFSVHQ MLKRFGNGSH TVVASLVTSS EGCPSTSAWR AIPSVIHHIE
GGDNNNTVAS AVEQAANLLN SEGSGQDLLI PIGLTELVKS ELIDLLVIFD DETNNIRLPQ
DFPLILRIHQ RQDHWQLSVR YPSPLFDTMV IDSFLSALHN LLSAVTKPSQ LVRDIELLPE
YQVAQLEKWN NTDGDYPTEK RLHHLFEEAA VRRPQHVALI CGDKRITYEE LNAMANRLAH
HLVSSGIQTE QLVGLFLDKT ELMIATILGI WKSGAAHVPI DPGYPDERVK FVLNDTKAQV
VIASQRHVDR LRAEAVGGQH LRIIGLESLF DNLAQQTQHS PETSGNLTHL PLNSKQLAYV
TYTSGTTGFP KGIYKEHTSV VNSITDLSAR YGVAGEDDEV ILVFSAYVFE PFVRQMLMAL
TTGNSLAIIS DEDKFDPDTL IPFIQKHKVT YIHATSSVLQ EYDFGSCPSL KRMILVGENL
TEPRYEALRQ RFKSRILNEY GFTESAFVTA LNIFEPTSQR KDMSLGRPVR NVKCYILDAN
LKRVPIGVTG ELHIGGLGIS RGYMNREELT RQKFLPNPYQ TDKERQRGVN STMYKTGDLA
RWLPSGEVEY LGRADFQIKL RGIRIEPGEI ESTLAMYPGI RASIVVSKKL LSQGQETIQD
HLVGYYVCDE GHIPEGDLLS FLEKKLPRYM VPTRLVQLAQ IPTNINGKAD LRALPAVEVA
VAPTHKQDGE RGNQLESDLA AIWGNILSVP AQDIGSESNF FRLGGHSIAC IQLIARVRQQ
LGQGITLEEV FQTKTLRAMA ALLSEKYTKA SNGTNGVTNG TAHVNGHAAN GHVSDSYVAS
SLQQGFVYHS LKNELSEAYT MQSMIHYGVP LKRDIYQAAW QRVQGEHPAL RLRFTWEAEV
MQIVDPKSEL DWRVVDWTDV SSREKQLVAL EQLQTEDLAK VYHLDKGPLM RLYLILLPDS
KYSCLFSCHH AILDGWSLPL LFNNVHQAYL DLVEGTASPV EQDATYLLGQ QYLQSHRDDH
LDFWAEQIGR IEERCDMNAL LNEASRYKVP LADYDQVREQ RQQTISLPWN NSMDAGVREE
LSSRGITLHS ILQTVWHLVL HSYGGGTHTI TGTTISGRHL PVPGIERSVG LFINTLPMIF
DHTVCQDMTA LEAIEHVQGQ VNAMNSRGNV ELGRMSKNDL KHGLFDTLFV LENYPNLDTE
QREKHEEKLK FTIKGGTEKL SYPLAVIAQE DGDSGCSFTL CYAGELFTDE SIQALLDTVR
DTLSDILGNI HAPIRNMEYL SSNQTAQLDK WNATAFEYPN TTLHAMFESE AQQKPDKVAV
VYEDIRLTYR ELNSRANALA FYLLSQAAIQ PNKLVGLIMD KSEHMITSIL AVWKTGGAYV
PIDPRYPDQR IQYILEDTAA LAVITDSPHI DRLRSITNNR LPVIQSDFAL QLPPSPVHPV
SNCKPSDLAY IMYTSGTTGN PKGVMVEHHG VVNLCVSLCR LFGLRNTDDE VILSFSNYVF
DHFVEQMTDA LLNGQTLVVL NDEMRGDKER LYRYIETNRV TYLSGTPSVI SMYEFDRFRD
HLRRVDCVGE AFSEPVFDKI RETFPGLIIN GYGPTEVSIT THKRPYPFPE RRTDKSIGCQ
LDNSTSYVLN DDMKRVPIGA VGELYLGGDG VARGYHNRPD LTADRFPANP FQTEQERLEG
RNARLYKTGD LVRWIHNANG DGEIEYLGRN DFQVKIRGQR IELGEIEAVL SSYPGIKQSV
VLAKDRKNDG QKYLVGYFVS SAGSLSAQAI RRFMLTSLPD YMVPAQLVPI AKFPVTVSGK
LDAKALPVPD DTVEDDIVPP RTEVERILAG IWSELLEIPV DRISIYSDFF SLGGDSLKST
KLSFAATRAL GVAVSVRNLF SHPTIEALSQ WIIRGSNEVK DVAVVKGGAS LDIPLSPAQE
RLMFIHEFGH SGEDTGAYNV PLQLQLHHDV CLESLEKALR DVVSRHEALR TLITRTQKSS
VHCQKILDAE EAQKLFSVDV LRLTSETEMQ GRMAESTAHA FKLDEELPIH VRLYQVVRDG
RTLSFASIVC HHLAFDAWSW DVFQRDLDAF YAVHTKHKAA ANLPTLRVQY KEYAIEHRRA
LRAEQHRVLA DYWLRKLSDM EASYLVPDRP RPAQFDYTGN DLQFSTTPET TAQLKELAKR
EGSSLYTVVA AAYFLLLYVY TNQRDITIGI PVAHRNHPDF ESVVGFFVNL LPLRVNVSQS
DIHGLIQAVQ KELVDAQIHQ DLPFQEITKL LHVQHDPSRH PLLQAVFNWE NVPANVHEEQ
LLQEYKPPSP LPSAAKFDLN VTVKESVNSL NVNFNYPTSL FEEETVQGFM ETFHLLLRQL
AHNKASTSLS KLSVEDGVLN PEPTNLQPSS RDSGNSLHGL FEDIVASTPD RIAIADGTRS
LSYSELNERA NQLVHLIISS ASIVADDRIA LLLDKSIDMV IALLAVWKAG AAYVPLDPTY
PSQRTELILE ESSARTLITT RKHTPRGGTV ANVPSVVLDS PETLACLNQQ SKENPTTSTQ
KPSDLAYVIF TSGTTGKPKG VLVEHQSVVQ LRNSLIERYF GETNGSHAVL FLSNYVFDFS
LEQLCLSVLG GNKLIIPPEE GLTHEAFYDI GRREKLSYLS GTPSVLQQIE LSRLPHLHMV
TAAGEEFHAS QFEKMRSQFA GQINNAYGIT ETTVYNIITT FKGDAPFTKA LCHGIPGSHV
YVLNDRLQRV PFNAVGELYL GGDCLARGYL NQDALTNERF IPNPFYEPKQ ASDSRPQRLY
KTGDLVRFRG PHHLEYLGRK DQQVKLRGFR IELSEVRDAV LAISAVKEAA VIPKYDEDGS
DSRRVSAIVC YYTLNAGTVC EASSIRDHLH ANLPPYMVPS QIHQLEGSLP VTVNGKLDLN
RLSTTQVSQP ELYTAPRNST EETLCQLWAS LLGVDHCGID DDLFARGGDS ISSLRLVGDI
YRALGRKVTV KDIYLHRSVR ALSENVLTDQ KDKGTLPASP PLQRAEQGQV EGDAPLLPIQ
DWFLSKPLDN PAYWNHCFTI RTGALSVEGL RGALKLLQER HDVLRLRLQR RDEGRHVQTF
ARDCAQPRLT VLDRRSFEDA EDVQEALCEI QSHFDLENGP LYTVAYIHGY EDGSARVWFA
CHHVMVDTVS WNIILQDLQA LYHGDSLGPK SSSVQQWSLA VSDYKMPLSE RAHWNVLRKT
VAQSFETLPI CMGGVLQCQE KFSRETTTAL LSKACPALDS GMHEILLMAV GSALQKAAGD
VPQVVTIEGH GREDTIDATL DVSRTVGWFT SMYPFEIPKV TDPAQGVVDV KEAMRRVPNR
GVGYGPAYGY GGSCLPAVSF NYLGRLDQAS SGAQRDWTLV MDEDEYPVGL CTSAEDSGRS
SSMVDFTFSI SGGQLVMDMS SSWGHGARNE FVRTVRNTLD DLIKTTSSRD FSAPLPPSDQ
ESSFTPYFVF EEGERHGAPL FLLPPGEGGA ESYFHNIVKG LPNRNLVVFN NHYREEKTLR
TIEALAEYYL SHIRSIQPEG PYHILGWSFG GILGLEAAKR LTGEGHKIAT LALIDPYFDI
PSASKAIGQP DDACVLDPIY HVYHPSPESF RTVSSLTNHI ALFKATETND QHGNATQQAL
YEWFATCPLN NLDKFLAADT IKVVPLEGTH FTWVHHPEQV RSMCTMLDEW LG
