PDBsum entry 4a6d

Transferase

PDB id: 4a6d

Contents

Protein chain

345 a.a.

Ligands

SAM

SO4 ×4

GOL

Metals

_ZN ×2

Waters ×67

PDB id:

4a6d

Name:

Transferase

Title:

Crystal structure of human n-acetylserotonin methyltransferase (asmt) in complex with sam

Structure:

Hydroxyindole o-methyltransferase. Chain: a. Synonym: n-acetyl serotonin methyltransferase, hiomt, acetylserotonin o-methyltransferase, asmt. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: leishmania tarentolae. Expression_system_taxid: 5689

Resolution:

2.40Å R-factor: 0.177 R-free: 0.204

Authors:

P.Legrand,A.Haouz,W.Shepard

Key ref:

H.G.Botros et al. (2013). Crystal structure and functional mapping of human ASMT, the last enzyme of the melatonin synthesis pathway. J Pineal Res, 54, 46-57. PubMed id: 22775292 DOI: 10.1111/j.1600-079X.2012.01020.x

Date:

01-Nov-11 Release date: 07-Nov-12

Protein chain

P46597  (ASMT_HUMAN) -  Acetylserotonin O-methyltransferase from Homo sapiens

Seq: 345 a.a.

Struc: 345 a.a.

Enzyme reactions

• Enzyme class: E.C.2.1.1.4 - acetylserotonin O-methyltransferase.
• Reaction: N-acetylserotonin + S-adenosyl-L-methionine = melatonin + S-adenosyl-L- homocysteine + H⁺

N-acetylserotonin + S-adenosyl-L-methionine (Bound ligand (Het Group name = SAM) corresponds exactly) = melatonin + S-adenosyl-L- homocysteine + H(+)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1111/j.1600-079X.2012.01020.x

J Pineal Res 54:46-57 (2013)

PubMed id: 22775292

Crystal structure and functional mapping of human ASMT, the last enzyme of the melatonin synthesis pathway.

H.G.Botros, P.Legrand, C.Pagan, V.Bondet, P.Weber, M.Ben-Abdallah, N.Lemière, G.Huguet, J.Bellalou, E.Maronde, P.Beguin, A.Haouz, W.Shepard, T.Bourgeron.

ABSTRACT

Melatonin is a synchronizer of many physiological processes. Abnormal melatonin signaling is associated with human disorders related to sleep, metabolism, and neurodevelopment. Here, we present the X-ray crystal structure of human N-acetyl serotonin methyltransferase (ASMT), the last enzyme of the melatonin biosynthesis pathway. The polypeptide chain of ASMT consists of a C-terminal domain, which is typical of other SAM-dependent O-methyltransferases, and an N-terminal domain, which intertwines several helices with another monomer to form the physiologically active dimer. Using radioenzymology, we analyzed 20 nonsynonymous variants identified through the 1000 genomes project and in patients with neuropsychiatric disorders. We found that the majority of these mutations reduced or abolished ASMT activity including one relatively frequent polymorphism in the Han Chinese population (N17K, rs17149149). Overall, we estimate that the allelic frequency of ASMT deleterious mutations ranges from 0.66% in Europe to 2.97% in Asia. Mapping of the variants on to the 3-dimensional structure clarifies why some are harmful and provides a structural basis for understanding melatonin deficiency in humans.