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Review
. 2021 Jul-Dec:788:108396.
doi: 10.1016/j.mrrev.2021.108396. Epub 2021 Oct 7.

Insights into S-adenosyl-l-methionine (SAM)-dependent methyltransferase related diseases and genetic polymorphisms

Jiaojiao Li  1 , Chunxiao Sun  2 , Wenwen Cai  2 , Jing Li  2 , Barry P Rosen  3 , Jian Chen  4
Affiliations
Review

Insights into S-adenosyl-l-methionine (SAM)-dependent methyltransferase related diseases and genetic polymorphisms

Jiaojiao Li et al. Mutat Res Rev Mutat Res. 2021 Jul-Dec.

Abstract

Enzymatic methylation catalyzed by methyltransferases has a significant impact on many human biochemical reactions. As the second most ubiquitous cofactor in humans, S-adenosyl-l-methionine (SAM or AdoMet) serves as a methyl donor for SAM-dependent methyltransferases (MTases), which transfer a methyl group to a nucleophilic acceptor such as O, As, N, S, or C as the byproduct. SAM-dependent methyltransferases can be grouped into different types based on the substrates. Here we systematically reviewed eight types of methyltransferases associated with human diseases. Catechol O-methyltransferase (COMT), As(III) S-adenosylmethionine methyltransferase (AS3MT), indolethylamine N-methyltransferase (INMT), phenylethanolamine N-methyltransferase (PNMT), histamine N-methyltransferase (HNMT), nicotinamide N-methyltransferase (NNMT), thiopurine S-methyltransferase (TPMT) and DNA methyltansferase (DNMT) are classic SAM-dependent MTases. Correlations between genotypes and disease susceptibility can be partially explained by genetic polymorphisms. The physiological function, substrate specificity, genetic variants and disease susceptibility associated with these eight SAM-dependent methyltransferases are discussed in this review.

Keywords: Genotypes; Methylation; Methyltransferases; Phenotypes; S-adenosyl-l-methionine; Single nucleotide polymorphisms.

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Conflict of interest statement

Declaration of Competing Interest

The authors state that they have no competing interests.

Figures

Fig. 1.
Fig. 1.. Publications on S-adenosyl l-methionine (SAM)-dependent methyltransferases in the past 30 years.
A database search (Web of Science, Thomson Reuters) was performed on 20 April 2021. Depicted is the total number of publications using the following search strategies: ‘catechol O-methyl transferase’ AND ‘polymorphism’; ‘As(III) S-adenosylmethionine methyltransferases’ AND ‘polymorphism’; ‘Histamine N-methyltransferase ‘AND ‘polymorphism’; ‘Indolethylamine N-methyltransferase’ AND ‘polymorphism’; ‘Nicotinamide N-methyltransferase’ AND ‘polymorphism’; ‘Phenylethanolamine N-Methyltransferase’ AND ‘polymorphism’; ‘Thiopurine methyltransferase’ AND ‘polymorphism’; and ‘DNA (cytosine-5)-methyltransferase’ AND ‘polymorphism’.
Fig. 2.
Fig. 2.. Human biosynthetic pathway for trace amines and catecholamines.
L-Phenylalanine is converted into l-tyrosine by the enzyme AAAH (aromatic amino acid hydroxylases). l-Tyrosine is converted into l-DOPA (l-dihydroxyphenylalanine) by the enzyme AAAH. l-DOPA is catalyzed to dopamine by the enzyme aromatic l-amino acid decarboxylase (AADC). Dopamine itself is also used as a precursor in the synthesis of the neuro-transmitters, norepinephrine and epinephrine. Dopamine is converted into norepinephrine by the enzyme dopamine β-hydroxylase (DBH) and inactivated by COMT Norepinephrine is converted into epinephrine by the enzyme PNMT with SAM as the cofactor. Epinephrine and norepinephrine are inactivated by COMT. [32,39,40].
Fig. 3.
Fig. 3.. Multiple sequence alignment of As (III) SAM methyltransferases.
Homo sapiens As(III) S-adenosylmethionine methyltransferase (AAI19639) was aligned with eukaryotic orthologues from Danio rerio (zAS3MT, NP_001034928), Rattus norvegicus (rAS3MT, NP_543166) and Cyanidioschyzon merolae (CmArsM, FJ476310). Black shading indicates conserved residues, grey shading indicates conservative replacements, * denotes conserved cysteine residues, # denotes polymorphic residues.
Fig. 4.
Fig. 4.
Pathways for the biosynthesis and metabolism of DMT. Tryptophan is converted to tryptamine by aromatic amino acid decarboxylase (AADC). Trytamine is dimethylated to first yield N-methyltryptamine (NMT) and then N,N-dimethyltryptamine (DMT) by indole-N-methyltransferase (INMT), using S-adenosyl-methionine (SAM) as the methyl source. Metabolism: tryptamine, NMT and DMT are all substrates for monoamine oxidase (MAO), yielding indole-3-acetic acid (IAA) as both a common precursor metabolite and the most abundant metabolite of DMT itself. DMT is also converted to DMT-N-oxide as the second-most abundant metabolite. Adapted and modified from [77].
Fig. 5.
Fig. 5.
Crystal structures of SAM-dependent MTases. (A) human DNMT1(646–1600) in complex with DNA;(B)DNMT3A-DNMT3L in complex with DNA containing two CpG sites;(C) human COMT with bound SAM and DNC;(D) As3MT; (E) human HNMT (Thr105 Polymorphic Variant) complexed with SAH and histamine. DOI: 10.2210/pdb1JQD/pdb; (F) human INMT with SAH. DOI: 10.10.2210/pdb2A14/pdb; (G) human NNMT. DOI: 10.10.2210/pdb2IIP/pdb; (H) Crystal structure of human PNMT complexed with SK&F 29661 and AdoHcy; (I) TPMT. DOI: 10.10.2210/pdb2BZG/pdb.
Fig. 6.
Fig. 6.
(A) A disulfide bond between Cys44 and Cys72 in the crystal structure of CmArsM with bound aromatic arsenical, phenylarsenite PhAs (III) (PDB entry 4kw7). The conserved cysteine residues are shown in ball-and-stick representation with atoms colored green (carbon), blue (nitrogen) or yellow (sulfur). The dark blue sphere is the As atom. The length of the disulfide bond is approximately 2.1 Å in the PhAs (III)-bound structure. (B) The overall structure of CmArsM consists of an N-terminal domain, an As(III) binding domain, and a C-terminal domain. The inset shows a close-up of the active site showing the four conserved cysteine residues represented by balls and sticks with atoms colored green (carbon), blue (nitrogen), red (oxygen), and yellow (sulfur). The purple sphere is the arsenic atom, and the SAH in the SAM binding site is represented by balls and sticks and with carbon colored magenta. As(III) is bound among conserved residues Cys44, Cys174, and Cys224. (C1) The As atom in the binding site consisting of Cys44, Cys174, and Cys224 is positioned near SAH in the SAM binding site. The distance between the sulfur atom of SAH and the As atom is 4.9 Å. (C2) Distances between the As atom and the sulfur atoms of SAM is 2.9 Å. The S-methyl group is poised for electron transfer from SAM to As(III).
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