Protein: N-(5-amino-5-carboxypentanoyl)-L-cysteinyl-D-valine synthase (ACV synthetase) (ACVS) (EC 6.3.2.26) (Delta-(L-alpha-aminoadipyl)-L-cysteinyl-D-valine synthetase) (Nonribosomal peptide synthetase acvA) (Penicillin biosynthetis cluster protein acvA) (B6HLU1)
Organism: Penicillium rubens (strain ATCC 28089 / DSM 1075 / NRRL 1951 / Wisconsin 54-1255) (Penicillium chrysogenum)
Function: Nonribosomal peptide synthetase; part of the gene cluster that mediates the biosynthesis of penicillin, the world's most important antibiotic. The first step of the pathway is performed by the trimodular NRPS acvA that produces the tripeptide N-[(5S)-5-amino-5-carboxypentanoyl]-L-cysteinyl-D-valine (LLD-ACV or ACV) via condensation of the 3 residues L-2-aminoadipate, L-cysteine and L-valine. The precursor amino acids for penicillin biosynthesis are withdrawn from the vacuolar amino acid pool by the MFS-type transporter penV. Each of the constituent amino acids of the tripeptide ACV are activated as aminoacyl-adenylates with peptide bonds formed through the participation of amino acid thioester intermediates. The tripeptide ACV is then cyclized to form isopenicillin N (IPN) by the isopenicillin N synthase ipnA that forms the beta-lactam nucleus. Finally, the alpha-aminoadipyl side chain is exchanged for phenylacetic acid by the isopenicillin N acyltransferase aatA to yield penicillin. This step occurs in the peroxisomal matrix and the penM and paaT transporters are involved in the isopenicillin N and phenylacetic acid import into the peroxisome, respectively.
Subcellular location: Cytoplasm, cytosol {ECO:0000269|PubMed:12223189}. Vacuole membrane {ECO:0000269|PubMed:1899377, ECO:0000269|PubMed:8416970}; Peripheral membrane protein {ECO:0000269|PubMed:8416970}. Note=Loosely attached to the vacuoles. {ECO:0000269|PubMed:8416970}.
Sequence: MGPSNPAMAYFKPSTRDTMDPCSGNAADGSIRVRFRGGIERWKECVNQVPERCDLSGLTTDSTRYQLASTGFGDASAAYQERLMTVPVDVHAALQELCLERRVSVGSVINFSVHQMLKGFGNGTHTITASLHREQNLQNSSPSWVVSPTIVTHENRDGWSVAQAVESIEAGRGSEKESVTAIDSGSSLVKMGLFDLLVSFVDADDARIPCFDFPLAVIVRECDANLSLTLRFSDCLFNEETICNFTDALNILLAEAVIGRVTPVADIELLSAEQKQQLEEWNNTDGEYPSSKRLHHLIEEVVERHEDKIAVVCDERELTYGELNAQGNSLARYLRSIGILPEQLVALFLDKSEKLIVTILGVWKSGAAYVPIDPTYPDERVRFVLDDTKARAIIASNQHVERLQREVIGDRNLCIIRLEPLLASLAQDSSKFPAHNLDDLPLTSQQLAYVTYTSGTTGFPKGIFKQHTNVVNSITDLSARYGVAGQHHEAILLFSACVFEPFVRQTLMALVNGHLLAVINDVEKYDADTLLPFIRRHSITYLNGTASVLQEYDFSDCPSLNRIILVGENLTEARYLALRQRFKNRILNEYGFTESAFVTALKIFDPESTRKDTSLGRPVRNVKCYILNPSLKRVPIGATGELHIGGLGISKGYLNRPELTPHRFIPNPFQTDCEKQLGINSLMYKTGDLARWLPNGEVEYLGRADFQIKLRGIRIEPGEIETMLAMYPRVRTSLVVSKKLRNGPEETTNEHLVGYYVCDSASVSEADLLSFLEKKLPRYMIPTRLVQLSQIPVNVNGKADLRALPAVDISNSTEVRSDLRGDTEIALGEIWADVLGARQRSVSRNDNFFRLGGHSITCIQLIARIRQRLSVSISVEDVFATRTLERMADLLQNKQQEKCDKPHEAPTELLEENAATDNIYLANSLQQGFVYHYLKSMEQSDAYVMQSVLRYNTTLSPDLFQRAWKHAQQSFPALRLRFSWEKEVFQLLDQDPPLDWRFLYFTDVAAGAVEDRKLEDLRRQDLTERFKLDVGRLFRVYLIKHSENRFTCLFSCHHAILDGWSLPLLFEKVHETYLQLLHGDNLTSSMDDPYTRTQRYLHAHREDHLDFWAGVVQKINERCDMNALLNERSRYKVQLADYDQVQEQRQLTIALSGDAWLADLRQTCSAQGITLHSILQFVWHAVLHAYGGGTHTITGTTISGRNLPILGIERAVGPYINTLPLVLDHSTFKDKTIMEAIEDVQAKVNVMNSRGNVELGRLHKTDLKHGLFDSLFVLENYPNLDKSRTLEHQTELGYSIEGGTEKLNYPLAVIAREVETTGGFTVSICYASELFEEVMISELLHMVQDTLMQVARGLNEPVGSLEYLSSIQLEQLAAWNATEAEFPDTTLHEMFENEASQKPDKIAVVYEETSLTYRELNERANRMAHQLRSDVSPNPNEVIALVMDKSEHMIVNILAVWKSGGAYVPIDPGYPNDRIQYILEDTQALAVIADSCYLPRIKGMAASGTLLYPSVLPANPDSKWSVSNPSPLSRSTDLAYIIYTSGTTGRPKGVTVEHHGVVNLQVSLSKVFGLRDTDDEVILSFSNYVFDHFVEQMTDAILNGQTLLVLNDGMRGDKERLYRYIEKNRVTYLSGTPSVVSMYEFSRFKDHLRRVDCVGEAFSEPVFDKIRETFHGLVINGYGPTEVSITTHKRLYPFPERRMDKSIGQQVHNSTSYVLNEDMKRTPIGSVGELYLGGEGVVRGYHNRADVTAERFIPNPFQSEEDKREGRNSRLYKTGDLVRWIPGSSGEVEYLGRNDFQVKIRGLRIELGEIEAILSSYHGIKQSVVIAKDCREGAQKFLVGYYVADAALPSAAIRRFMQSRLPGYMVPSRLILVSKFPVTPSGKLDTKALPPAEEESEIDVVPPRSEIERSLCDIWAELLEMHPEEIGIYSDFFSLGGDSLKSTKLSFMIHESFNRAVSVSALFCHRTVEAQTHLILNDAADVHEITPIDCNDTQMIPVSRAQERLLFIHEFENGSNAYNIDAAFELPGSVDASLLEQALRGNLARHEALRTLLVKDHATGIYLQKVLSPDEAQGMFSVNVDTAKQVERLDQEIASLSQHVFRLDDELPWEARILKLESGGLYLILAFHHTCFDAWSLKVFEQELRALYAALQKTKSAANLPALKAQYKEYALYHRRQLSGDRMRNLSDFWLRKLIGLEPLQLITDRPRPVQFKYDGDDLSIELSKKETENLRGVAKRCKSSLYVVLVSVYCVMLASYANQSDVSVGIPVSHRTHPQFQSVIGFFVNLVVLRVDISQSAICGLIRRVMKELVDAQLHQDMPFQEVTKLLQVDNDPSRHPLVQNVFNFESRANGEHDARSEDEGSLAFNQYRPVQPVDSVAKFDLNATVTELESGLRVNFNYATSLFNKSTIQGFLHTYEYLLRQLSELSAEGINEDTQLSLVRPTENGDLHLPLAQSPLATTAEEQKVASLNQAFEREAFLAAEKIAVVQGDRALSYADLNGQANQLARYIQSVSCIGADDGIALMLEKSIDTIICILAIWKAGAAYVPLDPTYPPGRVQLILEEIKAKAVLVHSSHASKCERHGAKVIAVDSPAIETAVSQQSAADLPTIASLGNLAYIIFTSGTSGKPKGVLVEQKAVLLLRDALRERYFGRDCTKHHGVLFLSNYVFDFSVEQLVLSVLSGHKLIVPPAEFVADDEFYRMASTHGLSYLSGTPSLLQKIDLARLDHLQVVTAAGEELHATQYEKMRRRFNGPIYNAYGVTETTVYNIIAEFTTNSIFENALREVLPGTRAYVLNAALQPVPFDAVGELYLAGDSVTRGYLNQPLLTDQRFIPNPFCKEEDIAMGRFARLYKTGDLVRSRFNRQQQPQLEYLGRGDLQIKMRGYRIEISEVQNVLTSSPGVREGAVVAKYENNDTYSRTAHSLVGYYTTDNETVSEADILTFMKARLPTYMVPSHLCCLEGALPVTINGKLDVRRLPEIINDSAQSSYSPPRNIIEAKMCRLWESALGMERCGIDDDLFKLGGDSITSLHLVAQIHNQVGCKITVRDIFEHRTARALHDHVFMKDSDRSNVTQFRTEQGPVIGEAPLLPIQDWFLSKALQHPMYWNHTFYVRTPELDVDSLSAAVRDLQQYHDVFRMRLKREEVGFVQSFAEDFSPAQLRVLNVKDVDGSAAVNEILDGWQSGFNLENGPIGSIGYLHGYEDRSARVWFSVHHMAIDTVSWQILVRDLQTLYRNGSLGSKGSSFRQWAEAIQNYKASDSERNHWNKLVMETASSISALPTSTGSRVRLSRSLSPEKTASLIQGGIDRQDVSVYDSLLTSVGLALQHIAPTGPSMVTIEGHGREEVDQTLDVSRTMGWFTTMYPFEIPRLSTENIVQGVVAVSERFRQVPARGVGYGTLYGYTQHPLPQVTVNYLGQLARKQSKPKEWVLAVGDNEFEYGLMTSPEDKDRSSSAVDVTAVCIDGTMIIDVDSAWSLEESEQFISSIEEGLNKILDGRASQQTSRFPDVPQPAETYTPYFEYLEPPRQGPTLFLLPPGEGGAESYFNNIVKRLRQTNMVVFNNYYLHSKRLRTFEELAEMYLDQVRGIQPHGPYHFIGWSFGGILAMEMSRRLVASDEKIGFLGIIDTYFNVRGATRTIGLGDTEILDPIHHIYNPDPANFQRLPSATDRIVLFKAMRPNNKYESENQRRLYEYYDGTRLNGLDSLLPSDSDVQLVPLTDDTHFSWVGNPQQVEQMCATIKEHLARY
InterPro domains: - IPR042099: ANL, N-terminal domain (homologous_superfamily) [292-704]
- IPR020806: Polyketide synthase-like, phosphopantetheine-binding domain (domain) [824-3066]
- IPR001031: Thioesterase (domain) [3530-3737]
- IPR000873: AMP-dependent synthetase/ligase domain (domain) [299-2822]
- IPR036736: ACP-like superfamily (homologous_superfamily) [813-3070]
- IPR045851: AMP-binding enzyme, C-terminal domain superfamily (homologous_superfamily) [705-2984]
- IPR029058: Alpha/Beta hydrolase fold (homologous_superfamily) [3513-3742]
- IPR023213: Chloramphenicol acetyltransferase-like domain superfamily (homologous_superfamily) [924-3243]
- IPR009081: Phosphopantetheine binding ACP domain (domain) [818-3066]
- IPR025110: AMP-binding enzyme, C-terminal domain (domain) [1809-2971]
- IPR020845: AMP-binding, conserved site (conserved_site) [450-2630]
- IPR010071: Amino acid adenylation domain (domain) [319-2907]
- IPR006162: Phosphopantetheine attachment site (ptm) [850-3036]
- IPR001242: Condensation domain (domain) [918-3500]
Gene Ontology annotations:
Molecular Function (MF): GO:0003674 (molecular function), GO:0003824 (catalytic activity), GO:0016874 (ligase activity), GO:0016879 (ligase activity, forming carbon-nitrogen bonds), GO:0016881 (acid-amino acid ligase activity)
Biological Process (BP): GO:0008150 (biological process), GO:0008152 (metabolic process), GO:0009987 (cellular process), GO:0009058 (biosynthetic process), GO:0044237 (cellular metabolic process), GO:0016999 (antibiotic metabolic process), GO:0044281 (small molecule metabolic process), GO:0006807 (nitrogen compound metabolic process), GO:0019748 (secondary metabolic process), GO:0071704 (organic substance metabolic process), GO:0044550 (secondary metabolite biosynthetic process), GO:0017000 (antibiotic biosynthetic process), GO:1901360 (organic cyclic compound metabolic process), GO:1901564 (organonitrogen compound metabolic process), GO:1901576 (organic substance biosynthetic process), GO:0044283 (small molecule biosynthetic process), GO:0072338 (lactam metabolic process), GO:0046483 (heterocycle metabolic process), GO:0006082 (organic acid metabolic process), GO:0030653 (beta-lactam antibiotic metabolic process), GO:0044249 (cellular biosynthetic process), GO:0034641 (cellular nitrogen compound metabolic process), GO:0043603 (amide metabolic process), GO:0006790 (sulfur compound metabolic process), GO:0042316 (penicillin metabolic process), GO:1901566 (organonitrogen compound biosynthetic process), GO:0072339 (lactam biosynthetic process), GO:1901362 (organic cyclic compound biosynthetic process), GO:0044272 (sulfur compound biosynthetic process), GO:0016053 (organic acid biosynthetic process), GO:0043436 (oxoacid metabolic process), GO:0018130 (heterocycle biosynthetic process), GO:0009308 (amine metabolic process), GO:0043604 (amide biosynthetic process), GO:0044271 (cellular nitrogen compound biosynthetic process), GO:0042318 (penicillin biosynthetic process), GO:0030654 (beta-lactam antibiotic biosynthetic process), GO:0019752 (carboxylic acid metabolic process), GO:0046394 (carboxylic acid biosynthetic process), GO:0072330 (monocarboxylic acid biosynthetic process), GO:0032787 (monocarboxylic acid metabolic process)
Cellular Component (CC): GO:0005575 (cellular component), GO:0110165 (cellular anatomical entity), GO:0005622 (intracellular anatomical structure), GO:0043226 (organelle), GO:0005737 (cytoplasm), GO:0016020 (membrane), GO:0005773 (vacuole), GO:0031090 (organelle membrane), GO:0043229 (intracellular organelle), GO:0043227 (membrane-bounded organelle), GO:0098588 (bounding membrane of organelle), GO:0043231 (intracellular membrane-bounded organelle), GO:0005774 (vacuolar membrane)