Here, we report a two-component enzymatic system that efficiently catalyzes the reduction of a carboxylate to an aldehyde in the biosynthesis of 2,2'-bipyridine antibiotics caerulomycins. The associated paradigm involves the activation of carboxylate by ATP-dependent adenylation protein CaeF, followed by its reduction catalyzed by CaeB2, a new class of NADPH-dependent aldehyde dehydrogenase (ALDH) that directly reduces AMP-conjugated carboxylate, which is distinct from the known aldehyde-producing enzymes that reduce ACP- or CoA-conjugated carboxylates.