ID   ACVA_HAPCH              Reviewed;        3712 AA.
AC   P25464;
DT   01-MAY-1992, integrated into UniProtKB/Swiss-Prot.
DT   01-MAY-1992, sequence version 1.
DT   04-NOV-2026, entry version 125.
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   Hapsidospora chrysogena (Acremonium chrysogenum).
OC   Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Sordariomycetes;
OC   Hypocreomycetidae; Hypocreales; Bionectriaceae; Hapsidospora.
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=L-2-aminoadipate + L-valine + L-cysteine + 3 ATP + H2O = N-
CC         [(5S)-5-amino-5-carboxypentanoyl]-L-cysteinyl-D-valine + 3 AMP + 3
CC         diphosphate + 3 H(+); 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   UniPathway; UPA00149; UER00239.
DR   GO; GO:0005829; C:cytosol; IEA:UniProtKB-SubCell.
DR   GO; GO:0005774; C:vacuolar membrane; ISS:UniProtKB.
DR   GO; GO:0050564; F:N-(5-amino-5-carboxypentanoyl)-L-cysteinyl-D-valine synthase activity; EXP:UniProtKB.
DR   GO; GO:0031177; F:phosphopantetheine binding; IEA:InterPro.
DR   GO; GO:0043041; P:amino acid activation for nonribosomal peptide biosynthetic process; IEA:TreeGrafter.
DR   GO; GO:0042318; P:penicillin biosynthetic process; ISS:GO_Central.
DR   CDD; cd17648; A_NRPS_ACVS-like; 3.
DR   CDD; cd19543; DCL_NRPS; 1.
DR   CDD; cd19534; E_NRPS; 1.
DR   CDD; cd19539; SgcC5_NRPS-like; 1.
DR   FunFam; 3.30.300.30:FF:000010; Enterobactin synthetase component F; 1.
DR   FunFam; 3.40.50.980:FF:000001; Non-ribosomal peptide synthetase; 3.
DR   FunFam; 1.10.1200.10:FF:000005; Nonribosomal peptide synthetase 1; 2.
DR   Gene3D; 3.30.300.30; -; 3.
DR   Gene3D; 3.40.50.980; -; 6.
DR   Gene3D; 1.10.1200.10; ACP-like; 3.
DR   Gene3D; 3.40.50.1820; alpha/beta hydrolase; 1.
DR   Gene3D; 3.30.559.10; Chloramphenicol acetyltransferase-like domain; 3.
DR   Gene3D; 2.30.38.10; Luciferase, Domain 3; 3.
DR   Gene3D; 3.30.559.30; Nonribosomal peptide synthetase, condensation domain; 4.
DR   InterPro; IPR010071; AA_adenyl_dom.
DR   InterPro; IPR029058; AB_hydrolase_fold.
DR   InterPro; IPR036736; ACP-like_sf.
DR   InterPro; IPR045851; AMP-b_sf.
DR   InterPro; IPR025110; AMP-bd_C.
DR   InterPro; IPR020845; AMP-binding_CS.
DR   InterPro; IPR000873; AMP-dep_synth/lig_dom.
DR   InterPro; IPR023213; CAT-like_dom_sf.
DR   InterPro; IPR001242; Condensation_dom.
DR   InterPro; IPR020806; PKS_PP-bd.
DR   InterPro; IPR009081; PP-bd_ACP.
DR   InterPro; IPR006162; Ppantetheine_attach_site.
DR   InterPro; IPR001031; Thioesterase.
DR   NCBIfam; TIGR01733; AA-adenyl-dom; 3.
DR   NCBIfam; NF003417; dltA; 3.
DR   PANTHER; PTHR45527:SF1; FATTY ACID SYNTHASE; 1.
DR   PANTHER; PTHR45527; NONRIBOSOMAL PEPTIDE SYNTHETASE; 1.
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; SSF56801; Acetyl-CoA synthetase-like; 3.
DR   SUPFAM; SSF47336; ACP-like; 3.
DR   SUPFAM; SSF53474; alpha/beta-Hydrolases; 1.
DR   SUPFAM; SSF52777; CoA-dependent acyltransferases; 7.
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
//