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ANALES?DE?LA?REAL?ACADEMIA?NACIONAL?DE?FARMACIA? Article

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The new levels of redox regulation of S-adenosylmethionine synthesis

Title in Spanish: Los nuevos niveles de regulación redox de la síntesis de S-adenosilmetionina

María Ángeles Pajares1,2*

1Departamento de Metabolismo y Señalización Celular, Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM),
Arturo Duperier 4, 28019, Madrid. 2Grupo de Hepatología Molecular, Instituto de Investigación Sanitaria del Hospital
Universitario La Paz (IdiPAZ), Paseo de la Castellana 261, 28046 Madrid.

ABSTRACT: S-adenosylmethionine is a very versatile RESUMEN: La S-adenosilmetionina es un compuesto

compound known to be involved in as many reactions as muy versátil, conocido por participar en casi tantas
ATP. Its role as methyl donor is key for the production reacciones como el ATP. Su papel como donante de
of a large variety of molecules, as well as, for the grupos metilo es esencial para la producción de una gran

modification of proteins and nucleic acids. Therefore, it variedad de moléculas, así como para la modificación de
is not surprising that impairments in the methionine proteínas y ácidos nucleicos. Por ello, no resulta
cycle are found in many diseases including liver sorprendente que se hayan detectado alteraciones en el

pathologies, Alzheimer or rare diseases. In most of these ciclo de la metionina en una gran variedad de
cases, reductions in S-adenosylmethionine patologías, que incluyen desde enfermedades hepáticas
concentrations correlate with the presence of oxidative hasta el Alzheimer o enfermedades raras. En muchos de

stress. This fact prompted the study of a putative redox estos casos la reducción de los niveles de S-
regulation of the methionine cycle that has been focused adenosilmetionina se acompaña de la presencia de estrés
especially on methionine adenosyltransferases, the oxidativo. Este hecho ha inducido el estudio de una

enzymes that synthesize S-adenosylmethionine. This posible regulación redox del ciclo de la metionina, que
review is intended to provide an outline of the new se ha enfocado principalmente a las metionina
levels at which the redox control of these enzymes is adenosiltransferasas, que son las enzimas encargadas de

exerted and their importance for liver pathology, a field la síntesis de S-adenosilmetionina. Esta revisión
in which we have made several key contributions. pretende dar una visión global de los nuevos niveles a
los que se ejerce el control redox de estas enzimas y su

importancia en hepatopatología, campo en el cual hemos
realizado importantes aportaciones.

*Corresponding Author: mapajares@iib.uam.es An Real Acad Farm Vol. 82, Nº 2 (2016), pp. 231-246

Received: October 7, 2015 Accepted: June 27, 2016 Language of Manuscript: English

Accésit Premio Real Academia Nacional de Farmacia del Concurso Científico 2015 de la Real Academia Nacional de

Farmacia

1. INTRODUCTION involve the use of SAM has increased along the years, so
that nowadays the catalogue of reactions using this
Nature has evolved to create several essential metabolite is as large as that of the processes utilizing ATP
compounds with high versatility, so that a few molecules (3). This versatility of SAM relies in its chemical structure,
can be used in a large variety of reactions. Initially, this which contains a quiral sulfonium group through which
represents an evolutionary advantage reducing the number carbon-sulfur bonds with aminopropyl, methyl and
of enzymes and compounds required for life. However, adenosine groups are established. These groups are
this same aspect imposes a serious drawback, since donated to a large variety of substrates upon nucleophilic
alterations affecting these few processes may lead to attack of the corresponding carbon-sulfur bond (reviewed
disease. Among these versatile compounds two have been in (4,5)). Additionally, SAM can also transfer the rybosyl
shown of special relevance for the cell, ATP and S- or amino groups in processes that have been described in
adenosylmethionine (SAM). This last metabolite was bacteria or plants (3,6,7).
described for the first time in 1951 by Cantoni as an
"active methionine" able to transmethylate in the absence Methyltransferases consume the majority of the SAM
of ATP (1). Although at that moment its exact nature was produced in any organism in reactions leading to the
unknown, in this same paper the author indicated that synthesis of small molecules (i.e. neurotransmitters,
SAM was a product of the reaction between ATP and phosphatidylcholine, etc.), the modification of proteins
methionine. Finally, in 1953 this researcher described the (i.e. histones) and DNA, among others. The remaining
reaction catalyzed by the "methionine activating enzyme" SAM is involved in the synthesis of 5'-halogenated
and the chemical nature of SAM (2). derivatives in marine organisms (adenosine group),
queuosine (rybosyl group) and other hypermodified
The number and variety of biological processes that
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@Real Academia Nacional de Farmacia. Spain