Multi-modular synthases

Multi-modular Synthases as Tools of the Synthetic Chemist... 

Many natural products are constrained by macrocyclic motifs, which are often essenhal for natural products to possess the desired biological properties. In the biosynthesis of macrocyclic NRPs and PKs, linear peptides or PKs are often mac-rocyclized by a TE domain located at the C-terminal of multi-modular synthases. For example, in the biosynthesis of the antibiotic tyrocidine A (Tyc A), a linear enzyme-bound decapephde, which is transferred from the last carrier protein (or thiolahon) domain of the Tyc A synthase, is cyclized by an intramolecular Sn2 reachon between the N-terminal amine nucleophile and the C-terminal ester, which is covalently linked to serine residual in the TE domain prior to macro-cyclization (Scheme 7.9) ([35] and references therein). 

Phosphopantetheine tethering is a posttranslational modification that takes place on the active site serine of carrier proteins - acyl carrier proteins (ACPs) and peptidyl carrier proteins (PCPs), also termed thiolation (T) domains - during the biosynthesis of fatty acids (FAs) (use ACPs) (Scheme 23), polyketides (PKs) (use ACPs) (Scheme 24), and nonribosomal peptides (NRPs) (use T domain) (Scheme 25). It is only after the covalent attachment of the 20-A Ppant arm, required for facile transfer of the various building block constituents of the molecules to be formed, that the carrier proteins can interact with the other components of the different multi-modular assembly lines (fatty acid synthases (FASs), polyketide synthases (PKSs), and nonribosomal peptide synthetases (NRPSs)) on which the compounds of interest are assembled. The structural organizations of FASs, PKSs, and NRPSs are analogous and can be divided into three broad classes the types I, II, and III systems. Even though the role of the carrier proteins is the same in all systems, their mode of action differs from one system to another. In the type I systems the carrier proteins usually only interact in cis with domains to which they are physically attached, with the exception of the PPTases and external type II thioesterase (TEII) domains that act in trans. In the type II systems the carrier proteins selectively interact... 

The third type of modularity, the multi-catalytic enzymes using substrate channelling, are of particular interest for synthetic applications. Prominent members are the fatty acid synthases, the polyketide synthases and the non-ribosomal peptide synthases l42-44 . in these large proteins, a number of catalytic domains is combined with accessory domains and allows the catalysis of an entire pathway by a single polypeptide chain. Multi-catalytic enzymes frequently use a swinging arm , which is covalently attached to the intermediary product of one reaction step, and is subsequently able to present this molecule to the next catalytic domain for further... 

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