Serotonin N-acetyltransferase

Function

Most organisms experience a 24-hr cycle due to the environmental dark/light cycle. Melatonin is one of the output signals which causes these rhythms. Circulating melatonin is higher at night acting as a downstream as well as a feedback signal for the biological clock ^[1]. Melatonin is produced in the pineal gland by two enzymes: 1) serotonin N-acetyltransferase or arylalkylamine N-acetyltransferase (AANAT) and hydroxyindole-O-methyltransferase (HIOMT). The AANAT catalyzes the transfer of an acetyl group from acetyl coenzyme A (AcCoA) to the primary amine of serotonin, producing the product, N-acetylserotonin, which is then methylated by HIOMT to produce melatonin. The determination of the structure of serotonin N-acetyltransferase is important in order to understand the nature of substrate binding and to know the mechanism of catalysis. Further, it helps in designing compounds that inhibit catalysis and prevent proteolysis for treatment of diseases which are melatonin-related (e.g. sleep disorder and jet lag) and serotonin-related (e.g.depression and obesity).

Structure

The structure of the uncomplexed form of serotonin N-acetyltransferase consists of eight beta strands that form a highly twisted beta-sheet and flanked by five alpha-helices. The beta strands are all anti-parallel except for strands beta 5 and beta 6. It can be viewed as two sheets sharing two central strands. A long alpha helix is present at the concave surface (PDBID:1b6b). The structure of when bound to the bisubstrate analog consists of seven beta strands and five alpha helices. Upon , there is a large conformational change in the enzyme; a small beta strand (strand beta 2) is gone, and an is extended in that region. The bisubstrate analog is . It has the same structure as serotonin except for a hydroxy group at the 5-position of the indole ring. The size and shape of the fit into the protein's cavity and the analog is held in an conformation. It is stabilized by three : , , and . The indole ring of the tryptamine group is stabilized by hydrophobic interactions with , , , , , and forming a pocket for serotonin-binding site. ^[1] and are conserved residues in the active site ^[2].

Implications for Catalysis

Water molecules lying between the tryptamine moiety and histidines facilitate nucleophilic attack on Acetyl Coenzyme-A (AcCoA). It can either serve as a sink for a proton or as a pathway to carry the charge away from the substrates.

Relevance

SNA inhibitors have therapeutical applications in maintaining cell level of melatonin which is varying in various diseases^[3].

3D structures of serotonin N-acetyltransferase

Updated on 20-March-2022

1b6b – sSNA – sheep

1cjw – sSNA + CoA S-acetyl tryptamine

1kuv - sSNA (mutant) + CoA S-acetyl bromotryptamine

1kux - sSNA (mutant) + CoA S-trimethylene-acetyl tryptamine

1kuy, 1l0c - sSNA (mutant) + CoA S-acetyl tryptamine

1ib1 – sSNA + protein kinase C inhibitor protein-1

6k5m, 7dai – SNA – rice
7daj – rSNA + acetyl CoA
7dal – rSNA + acetyl CoA + serotonin
7dak – rSNA + acetyl CoA + methoxytriptamine

See Also

• Molecule of the Month (Jan. 2008)

References

1. ↑ ^{1.0 1.1} Hickman AB, Namboodiri MA, Klein DC, Dyda F. The structural basis of ordered substrate binding by serotonin N-acetyltransferase: enzyme complex at 1.8 A resolution with a bisubstrate analog. Cell. 1999 Apr 30;97(3):361-9. PMID:10319816
2. ↑ Hickman AB, Klein DC, Dyda F. Melatonin biosynthesis: the structure of serotonin N-acetyltransferase at 2.5 A resolution suggests a catalytic mechanism. Mol Cell. 1999 Jan;3(1):23-32. PMID:10024876
3. ↑ Zheng W, Cole PA. Serotonin N-acetyltransferase: mechanism and inhibition. Curr Med Chem. 2002 Jun;9(12):1187-99. PMID:12052171