Short-chain dehydrogenase/reductase; 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:28777910, PubMed:31548667). 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). The first reaction catalyzed is a NADPH-dependent reduction reaction in which the nicotinamide cofactor is a stoichiometric reagent (PubMed:31548667). Either NADH or NADPH is effective as a cofactor (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:28777910, PubMed:31548667). 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-hydroxy-3-{[2-(1,1-dimethylallyl)-indol-3-yl]methyl}-6H,7H,8H-5lambda(5)-pyrrolo[1,2-a]pyrazine + H(+) + NADPH = 1-hydroxy-3-{[2-(1,1-dimethylallyl)-indol-3-yl]methyl}-4H,6H,7H,8H-pyrrolo[1,2-a]pyrazine + NADP(+) 1-hydroxy-3-{[2-(1,1-dimethylallyl)-indol-3-yl]methyl}-4H,6H,7H,8H-pyrrolo[1,2-a]pyrazine = (+)-premalbrancheamide NADP(+) is required for stereocontrolled formation of premalbrancheamide, however it does not appear to be required as a formal stoichiometric reagent because the second reaction performed by malC, the [4+2] cycloaddition, is a balanced chemical reaction without requirement for hydride transfer to balance the reaction (Probable). Alkaloid biosynthesis. Malbrancheamides have the ability to inhibit calmodulin, calmodulin-dependent phosphodiesterase (PDE1), and induce both endothelium-independent and endothelium-dependent relaxant effects, suggesting their potential as vasorelaxant agents. Belongs to the short-chain dehydrogenases/reductases (SDR) family. MalC lacks the characteristic Tyr and Lys catalytic amino acids, and also the essential Asn and Ser residues of typical SDR family proteins, suggesting that the active site is reconfigured to fit its unique catalytic roles.