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Actinomycins peptide synthetases

Like modular PKSs, peptide synthetases also epimerize some substrates and/or intermediates. For example, the starter substrate amino acid of cyclosporin A is D-Ala. Racemization of alanine is not catalyzed by an integrated subunit of cyclosporin A synthetase, but by alanine racemase. This is a separate, pyridoxal phosphate-dependent enzyme [ 193]. In contrast, Grsl and Tycl covalently activate L-Phe as a thioester and subsequently epimerize the amino acid [194]. D-Phe is the only epimer accepted as a substrate for dipeptide formation by Grs2 and Tyc2 [195, 196]. No racemization activity is detected in a pantetheine-deficient mutant of Grsl [197]. Deletion mutagenesis pointed to the requirement of the COOH-terminal part of the module for epimerizing L-Phe to D-Phe [180]. In contrast, the biosynthesis of actinomycin D, a bicyclic chromo-pentapeptide lactone (Fig. 10), involves formation of the dipeptide 6-MHA (methylanthranilic acid)-L-Thr-L-Val prior to epimerization of the L-Val exten-... [Pg.119]

Many NRPs such as cyclosporin, complestatin, actinomycin, and chondramide contain N-methyl amides. M-Methyl transferase (N-MT) domains utilize S-adenosylmethionine (SAM) as a cofactor to catalyze the transfer of the methyl group from SAM to the a-amine of an aminoacyl-S-PCP substrate. The presence of M-methylamides in NRPs is believed to protect the peptide from proteolysis. Interestingly, N-MT domains are incorporated into the A domains of C-A-MT-PCP modules, between two of the core motifs (A8 and A9). MT domains contain three sequence motifs important for catalysis. ° 0-Methyl transferase domains are also found in NRPSs and likewise use the SAM cofactor. For instance, cryptophycin and anabaenopeptilide synthetases contain 0-MT domains for the methylation of tyrosine side chains. These 0-MT domains lack one of the three core motifs described for N-MT domains. ... [Pg.635]

The thiol-template mechanism is utilized in other enzymes involved in production of peptide-based antibiotics. Actinomycin synthetase II (ACMSII) and b-L-(a-aminoadipolyl)-L-cysteinyl-D-valine (ACV) synthetase catalyze the stereoinversion of valine residues vithin peptide-based antibiotics, and employ ATP and the PAN cofactor in a mechanism similar to that depicted in Fig. 7.14 [58, 59]. ACMSII catalyzes the stereoinversion of a valine within the tripeptide 4-MHA-L-Thr-D-Val (MHA, 4-methyl-3-hydroxyanthranilic acid), which is a precursor for the antibiotic actinomycin D. ACV synthetase catalyzes the stereoinversion of the valine within ACV, which is a precursor for penicillin and cephalosporin [60-63]. ACV synthetase has been shown to have much broader substrate specificity, also accepting non-natural substrates [64, 65]. [Pg.1156]

The pentapeptide moiety is not attached to the cromophore until acti-nocin is formed. In Str. chrysomallus, the whole enzyme complex responsible for the modification and polymerisation of the aminoacids which constitute the peptide chain has been isolated and characterised as being composed of three fractions (actinomycin synthetase I, II, and III) [183-184]. [Pg.1010]

From all data available so far on peptide and depsipeptide synthetases, it af >ears that enzymes of bacterial origin such as gramicidin 5 synthetase, tyrocidine synthetase, or actinomycin synthetase (all reviewed in Ref. 61) have subunit structure, whereas fungal enzymes such as SDZ 214-103 synthetase (62) (see Section VI.C), SDZ 90-215 synthetase (63), and cyclosporin synthetase consist of single polypeptide chains. Cyclospcmn synthetase represents the most complex one. Like type 1 polyketide synthases, these enzymes are designated multifunctional polypeptides the bacterial enzymes, on the other hand, are called "multienzyme complexes, analogous to type 11 polyketide synthases (64). [Pg.289]

Keller U- Actinomycin synthetases Multifunctional enzymes responsible (or the synthesis of the peptide chains of actinomycin. J Biol Chem 1987 262 5852-5856. [Pg.358]


See other pages where Actinomycins peptide synthetases is mentioned: [Pg.477]    [Pg.479]    [Pg.491]    [Pg.339]    [Pg.342]    [Pg.419]    [Pg.199]    [Pg.229]    [Pg.229]    [Pg.337]    [Pg.346]    [Pg.347]    [Pg.347]    [Pg.163]    [Pg.326]   
See also in sourсe #XX -- [ Pg.336 , Pg.419 ]




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