5wgt
Crystal Structure of MalA' H253A, premalbrancheamide complex
Structural highlights
FunctionMALA_MALAU Flavin-dependent halogenase; part of the gene cluster that mediates the biosynthesis of malbrancheamide, a dichlorinated fungal indole alkaloid that belongs to a family of natural products containing a characteristic bicyclo[2.2.2]diazaoctane core (PubMed:23213353, PubMed:31548667, PubMed:28777910). The first step of malbrancheamide biosynthesis involves coupling of L-proline and L-tryptophan by malG, a bimodular NRPS, to produce L-Pro-L-Trp aldehyde through reductive offloading (PubMed:23213353, PubMed:31548667). This compound undergoes spontaneous cyclization and dehydration to give a dienamine which is reverse prenylated at C-2 by malE (PubMed:31548667). The other prenyltransferase present in the cluster, malB, displays modest activity, suggesting that may be a redundant gene in the pathway (PubMed:31548667). Subsequently, a [4+2] Diels-Alder cyclo-addition catalyzed by the bifunctional enzyme malC forms the characteristic bicyclo[2.2.2]diazaoctane ring of premalbrancheamid (PubMed:31548667). Finally, the flavin-dependent halogenase malA catalyzes the iterative dichlorination of the indole ring of premalbrancheamide to yield C-9 monochlorinated malbrancheamide B, C-8 monochlorinated isomalbrancheamide B, and dichlorinated malbrancheamide (PubMed:31548667, PubMed:28777910). MalA is also able to brominate premalbrancheamide at C-9 to yield malbrancheamide C, and, to a lesser extend, at C-8 to yield isomalbrancheamide C (PubMed:28777910). Finally, malA can brominate C-9 monochlorinated malbrancheamide B at C-8 to yield malbrancheamide D, or C-8 monochlorinated isomalbrancheamide B at C-9 to produce isomalbrancheamide D (PubMed:28777910).[1] [2] [3] Publication Abstract from PubMedMalbrancheamide is a dichlorinated fungal indole alkaloid isolated from Malbranchea aurantiaca that belongs to a family of natural products containing a characteristic bicyclo[2.2.2]diazaoctane core. The introduction of chlorine atoms on the indole ring of malbrancheamide differentiates it from other members of this family and contributes significantly to its biological activity. In this study, we characterized the flavin-dependent halogenase involved in the late-stage halogenation of malbrancheamide. MalA catalyzes the iterative dichlorination and monobromination of the free substrate premalbrancheamide as the final steps in the malbrancheamide biosynthetic pathway. Two unnatural bromo-chloro-malbrancheamide analogs were generated through MalA-mediated chemoenzymatic synthesis. Structural analysis and computational studies of MalA in complex with three substrates revealed that the enzyme represents a new class of zinc-binding flavin-dependent halogenases, and provides new insights into a potentially unique reaction mechanism. Function and structure of MalA/MalA', iterative halogenases for late-stage C-H functionalization of indole alkaloids.,Fraley AE, Garcia-Borras M, Tripathi A, Khare D, Mercado-Marin EV, Tran H, Dan Q, Webb G, Watts K, Crews P, Sarpong R, Williams RM, Smith JL, Houk KN, Sherman DH J Am Chem Soc. 2017 Aug 4. doi: 10.1021/jacs.7b06773. PMID:28777910[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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