Serotonin N-acetyltransferase
From Proteopedia
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==Structure== | ==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. The central fold and the "V" in the center of the sheet forms the AcCoA binding site. His-120, His-122, and Tyr-168 are in the active site. The structure of <scene name='Serotonin_N-acetyltransferase/Monomer/4'>Serotonin N-acetyltransferase bound with the bisubstrate analog </scene> consists of seven beta strands and five alpha helices. The bisubstrate analog is <scene name='Serotonin_N-acetyltransferase/Analog/1'>Coenzyme A-S-acetyltryptamine</scene>. 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 <scene name='Serotonin_N-acetyltransferase/Analog2/3'>analog</scene> fits into the protein's cavity and is held in an <scene name='Serotonin_N-acetyltransferase/Analog2/4'>"S" shaped</scene> conformation. It is stabilized by three hydrogen bonds: <scene name='Serotonin_N-acetyltransferase/Hbond/1'>Tyr-168</scene | + | 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. The central fold and the "V" in the center of the sheet forms the AcCoA binding site. His-120, His-122, and Tyr-168 are in the active site. The structure of <scene name='Serotonin_N-acetyltransferase/Monomer/4'>Serotonin N-acetyltransferase bound with the bisubstrate analog </scene> consists of seven beta strands and five alpha helices. The bisubstrate analog is <scene name='Serotonin_N-acetyltransferase/Analog/1'>Coenzyme A-S-acetyltryptamine</scene>. 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 <scene name='Serotonin_N-acetyltransferase/Analog2/3'>analog</scene> fits into the protein's cavity and is held in an <scene name='Serotonin_N-acetyltransferase/Analog2/4'>"S" shaped</scene> conformation. It is stabilized by three <scene name='Serotonin_N-acetyltransferase/Hbond/2'>hydrogen bonds</scene>: <scene name='Serotonin_N-acetyltransferase/Hbond/1'>Tyr-168</scene>, <scene name='Serotonin_N-acetyltransferase/Hbond2/1'>Leu-124</scene>, and <scene name='Serotonin_N-acetyltransferase/Hbond3/1'>Met-159 </scene>. 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. <ref name="analog" /> |
==References== | ==References== | ||
<references /> | <references /> | ||
Revision as of 05:13, 15 December 2009
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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
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. The central fold and the "V" in the center of the sheet forms the AcCoA binding site. His-120, His-122, and Tyr-168 are in the active site. The structure of consists of seven beta strands and five alpha helices. 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 fits into the protein's cavity and is held in an conformation. It is stabilized by three : , , and . 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
- ↑ 1.0 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
