The structural basis of ordered substrate binding by serotonin N-acetyltransferase: enzyme complex at 1.8 A resolution with a bisubstrate analog.
Serotonin N-acetyltransferase, a member of the GNAT acetyltransferase superfamily, is the penultimate enzyme in the conversion of serotonin to melatonin, the circadian neurohormone. Comparison of the structures of the substrate-free enzyme and the complex with a bisubstrate analog, coenzyme A-S-acetyltryptamine, demonstrates that acetyl coenzyme A (AcCoA) binding is accompanied by a large conformational change that in turn leads to the formation of the serotonin-binding site. The structure of the complex also provides insight into how the enzyme may facilitate acetyl transfer. A water-filled channel leading from the active site to the surface provides a pathway for proton removal following amine deprotonation. Furthermore, structural and mutagenesis results indicate an important role for Tyr-168 in catalysis.
D000105:Acetyl Coenzyme A / Q000737:chemistry / Q000378:metabolism; D000107:Acetylation; D000121:Acetylserotonin O-Methyltransferase / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001191:Arylamine N-Acetyltransferase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites / Q000502:physiology; D002384:Catalysis; D003001:Cloning, Molecular; D008550:Melatonin / Q000096:biosynthesis; D008969:Molecular Sequence Data; D016296:Mutagenesis / Q000502:physiology; D017433:Protein Structure, Secondary; D012756:Sheep; D013379:Substrate Specificity; D014363:Tryptamines / Q000737:chemistry / Q000378:metabolism