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Multidomain Enzymes Involved in Peptide Synthesis

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Multidomain Enzymes Involved in Peptide Synthesis Volume 307,number 1,40-43 FEBS 11171 July 1992 0 1992 Federalion of European Biochemical Societies 00145793/92/$S.O0 Multidomain enzymes involved in peptide synthesis Mohamed A. Marahiel Biuclrentic/~B Cllentie. Hems-Mc~r~uetrz-Sr~u~~,Plriitpps Lhivrrsirltr Marbwg, W-3550 Murbrrrg, Gerrnuny Received 3 April 1992 Biosynthesis of peptidcs in non-ribosomal systems is catalyzed by multifunctional enzymes that employ ~hcthio-template mechanism. Recent studies on the analysis of the primary structure of several peptidc wynthetascs have rcvcalcd that they are organized in highly conserved and repeated functional domains. The aligned domains provide the template for peptidc synthesis, and their order determines the sequence of the pcptide product. Multidomain enzyme; Peptide synthctasc: Thio-template; Core sequence 1. INTRODUCTION leased from the multi-enzyme either by cyclization or by the action of a specific thioesterase, This polymerization Bioactive pcptides with linear and cyclic structures mechanism links non-ribosomal peptide synthesis to are produced non-ribosomally by several bacterial and that of fatty acid and polyketide synthesis. The protein- fungal species with the aid of multi-enzyme complexes thio-template pathway has been shown to direct the [I], Over 20 years ago Fritz Lipmann [2,3] proposed that synthesis of gramicidin S, tyrocidine, surfactin, baci- the multi-enzyme peptide synthetases employ the thio- tracin, enniatin, actinomycin, cyclosporin, and also the template mechanism in the synthesis of these peptides. first step in ,!%lactam biosynthesis, the condensation of The constituents of the peptides, amino- and hydroxy the tripeptide &(I_-a-aminoadipoyl)-L-cysteinyl-D-valine acids, that have to be sequentially connected by the (ACV) (for review see [l,lO-121). corresponding peptide synthetase are first activated as acyl adcnylates where ATP serves as the energy source. This activation is similar to that catalyzed by the ami- 2. GENES ENCODING MULTIFUNCTIONAL noacyl-tRNA synthetases [4], however, no tRNA inter- PEPTIDE SYNTHETASES mediates are formed, but instead peptide synthetases covalently link the activated amino acid as a carboxy Genes encoding multifunctional peptide synthetases thioestcr [5-71. of prokaryotes and lower eukaryotes have been recently For peptide synthetases activating more than one isolated and characterized. The primary structure and amino acid residue individual sites catalyzing the activa- gene organization of the operons encoding peptide syn- tion reactions were proposed to be attached on the thetases for the Bacillus cyclic peptide antibiotics gram- multi-enzyme complex in the same order in which their icidin S (grs), tyrocidine (rye) and surfactin (srf), have activated residues are incorporated into the growing been analysed in more detail [13-l 71. The entire nuclco- peptide chain. These distinct sites are referred to as tide sequence of the grs operon, which comprises the ‘domains’. Thus, the domains of the multi-enzyme pro- three genes grsT, gwl and g&3 on a 19 kb DNA frag- vide the template for the pre-defined peptidc sequence. ment, has been determined [18]. The gramicidin S syn- The elongation reaction is catalyzed by the enzyme thetase 1 (GrsA), which activates and racemises the first bound cofactor 4’-phosphopantetheine [8,9]. The acti- amino acid, Phe, is a protein composed of 1,098 amino vated amino acid bound as carboxy thioester to the acid residues with a calculated molecular weight of synthetase domain is then transferred to the thiol group 126,663 Da. The synthetase 2 (GrsB) is a single polypep- of the cofactor which acts as an internal transport sys- tide chain composed of 4,452 amino acids in length tem. In repeated trans-peptidation and trans-thiolation (510,287 Da) and activates the four amino acids, Pro, reactions the peptide chain is completed and then re- Val, Orn and Leu. The role of the grsT gene product in peptide synthesis is unknown. I-Iowever, the grsT-en- Cortwpmkrwe addrcss: BiochemielFB Chemie, Hans-Mrerwein- coded 29,000 Da protein shows striking homology to StraOc, Philipps IJnivrrsitU Murburg, W-3550 Marburg, Germany. fatty acid thioesterases of mammalian origin [14]. In Fax: (49) (6421) ?85 547. addition, the thioesterase active site (GHSXG) was also Volume 307, number 1 FEBS LETTERS July 1992 found within acyltransferases, which may suggest for degree of homology (35% identity) to the product of an GrsT a thioesterase- or an acyltransferase-like function open reading frame (orfx) associated with the grs in the non-ribosomal peptide synthesis. Support for this operon [30]. The function of sfpor orfx products is not can also be inferred from studies on the bap gene cluster known. In contrast, srfA+ which covers a DNA region and ACV synthetase. The bup gene cluster encodes en- of about 25 kb, contains 4 offs which encode three zymes involved in the synthesis of the tripeptide antibi- putative multi-enzymes and a thioesterase-like protein. otic, bialaphos, in Srrepronzyces hygroscopicus [19]. Two Grandi and co-workers [31] determined the entire nucle- open reading frames of the hap operon encode two pu- otide sequence of the srf operon and discovered seven tative thioesterases homologous to GrsT (30% identity). homologous and repeated domains similar to those Furthermore, the ACV synthetase contains at its car- identified in the grs and rye operons. These domains are boxy terminus an integrated domain homologous to the located in three orfs which are responsible for the acti- above mentioned thioesterases [20]. Also, recent studies vation of three, three and one amino acid, respectively. on the purified GrsT protein show that it stimulates The third locus, srffl, was found to be identical with an gramicidin S synthesis in vitro, however, GrsT at high early competence gene of d subril’is, cot?tA. cowA en- concentration slightly inhibits synthesis (T. Stachelhaus codes a response regulator protein which, when ncti- and M.A. Marahiel, unpublished results). Therefore, it vated by the gene product of cuntP, a histidine protein is tempting to speculate that GrsT may have a thio- kinase, acts as a positive transcriptional regulator of esterase function that is involved in correcting errant srfA. The gene products c?conrP and cornA are thought amino acylation in pcptide synthesis. to be two component regulatory partners of the sensor- Analysis of the primary structures of GrsA and GrsB regulator type [32]. derived from the nucleotide sequences revealed the pres- A multifunctional peptide synthetase similar IO those ence of five distinct homologous domains, each about identified in Bacillus species was also discovered in sev- 600 amino acid residues in length. The domains show eral /?-lactam producers of fungal and bacterial origin. about 4S-SO% identity and are separated by non-ho- The first step in the biosynthesis ofp-lactam antibiotics, mologous regions of about 500 amino acids [IS]. Four such as cephamycin, cephalosporin and penicillin, is domains are located within the GrsB sequence and in catalyzed by the formation of the tripeptide &+.-a-ami- the same order as the constituent amino acids Pro, Val, noadipyl)-L-cysteinyl-n-valine (ACV). The gene encod- Orn and Leu, which are incorporated into the growing ing ACV synthetase, pcbAB, has been isolated from the peptide chain (Fig. 1A). This is in agreement with the Gram-positive bacteriae species, Ftavobacreriurn. Srrep- biochemical data obtained from proteins encoded by cornyces cbvoligerus and Nocurdia lacramiwatts [33,34], the grsB domains and from the proteolytic analysis of as well as from the fungi, Prnicilliutn chrysogemm [20], cleaved GrsB fragments [2 i-243. CephuCosporium ctcretnoniurn [35,36], and Aspergilh For tyrocidine synthesis three multi-enzymes are nidulurzs[37]. The ACV synthetase from p-lactam pro- needed: TycA, TycB and TycC [25]. TycA has a high ducers of prokaryotic and eukaryotic origin is encoded degree of homology to GrsA and also activates and by a single gene (pcbAB) located within a gene cluster racemises phenylalanine. The multi-enzymes, TycB and encoding other enzymes needed in @actam synthesis. TycC, synthesize the tripeptide, Pro-Phe-o-Phe, and the The pcbAB gene encodes a large protein of more than hexapeptide, Asn-Gin-Tyr-Val-Orn-Leu, respectively. 3,700 amino acid residues with a similar sequence and Based on biochemical studies and analysis of the pri- organization as the bacterial peptide synthetases in- mary structure it can be concluded that the mechanism volved in gramicidin S and tyrocidine synthesis. Three of tyrocidine synthesis is the same as that employed by homologous and repeated domains are located within gramicidin S peptide synthetases. The tyc genes contain the ACV synthetase sequence and are thought to be homologous domains and are organized in a large involved in the condensation of aminoadipate, L-cyste- operon in the order tycA-ryc&ycC [1 51.The operon is ine and D-valine to produce the tripeptide precursor for regulated at the transcriptional level from a promotor penicillin G. located at the 5’.end of rycA, which is under the control of the spoOA-abr8 system [26]. AbrB, a 10.7 kDa pro- 3. A CONSERVED FUNCTIONAL DOMAIN tein, acts as a negative regulator by direct interaction with sequences upstream and downstream of the tyc The domains of peptide synthetases seem to represent promotor, whereas SpoOA, a 29 kDa protein, is an the functional units and are believed to be the sites of ambivalent transcriptional regulator, negatively affect- amino acid activation and thioester formation. Exten- ing abrB transcription at the onset of stationary growth sive homology (35-50% identity) is observed between [27,28]. domains of different peptide synthetases, irrespective of Genetic studies in B. subtilis on the production of the their origin, over a region of about 600 amino acids [lS]. lipopeptide antibiotic, surfactin, identified three loci In addition, in all domains several highly conserved and (sfp, srfA, srfB) essential for its production [29]. The sfp potentially important motifs [Core sequences, Fig:.
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