Serotonin N-acetyltransferase

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Serotonin N-acetyltransferase

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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. (insert the picture from the article). 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 (depression and obesity).

Structure

There are several structures of this enzyme in the pdb. Two of them are the following: 1b6b: uncomplexed form 1cjw: bisubstrate analog-AANAT complex form The structureSCENE1 of the uncomplexed form 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 b5 and b6. It can be viewed as two sheets sharing two central strands; a long alpha helix is present at the concave surface. The central fold and the "V" in the center of the sheet forms the AcCoA binding site. It also has three loops. Histidines and Tyr-168 are in the active site. The bisubstrate analog is the CoA-S-acetyltryptamine. It has the same structure as serotonin except for a hydroxy group at the 5-position of the indole ring. The structure of the consists of seven beta strands and five alpha helices. The analogSCENE3's size and shape fits into the protein's conformation. It is stabilized by three hydrogen bonds: Tyr-168, Leu-124, and Met-159. The indole ring of the tryptamine group is stabilized by hydrophobic interactions with Phe-56, Pro-64, Meth-159, Val-183, Leu-186, and Phe-188 forming a hydrophobic pocket for serotonin-binding site. [1]

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

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Michal Harel, Kristine Faye Pobre, Alexander Berchansky

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