Radical S-Adenosylmethionine Enzymes in Human Health and Disease

Abstract

Radical S-adenosylmethionine (SAM) enzymes catalyze an astonishing array of complex and chemically challenging reactions across all domains of life. Of approximately 114,000 of these enzymes, 8 are known to be present in humans: MOCS1, molybdenum cofactor biosynthesis; LIAS, lipoic acid biosynthesis; CDK5RAP1, 2-methylthio-N(6)-isopentenyladenosine biosynthesis; CDKAL1, methylthio-N(6)-threonylcarbamoyladenosine biosynthesis; TYW1, wybutosine biosynthesis; ELP3, 5-methoxycarbonylmethyl uridine; and RSAD1 and viperin, both of unknown function. Aberrations in the genes encoding these proteins result in a variety of diseases. In this review, we summarize the biochemical characterization of these 8 radical S-adenosylmethionine enzymes and, in the context of human health, describe the deleterious effects that result from such genetic mutations.

Does Viperin Function as a Radical S-Adenosyl-l-methionine-dependent Enzyme in Regulating Farnesylpyrophosphate Synthase Expression and Activity?

“…Another pertinent, and better understood, example of a human enzyme in which both radical SAM and non-radical activities have been posited is the ELP3 (elongator protein 3) component of the RNA polymerase II complex (23). The elongator complex comprises six proteins, ELP1-6, and is responsible both for histone acetylation to facilitate transcription and for the modification of the wobble position U-34 of eukaryotic tRNAs by carbamoylmethylation or methoxy-carbonylmethylation at C-5 of uridine (35,36).…”

“…It is one of eight putative radical SAM enzymes identified in humans; four of these appear to be involved in tRNA modifications, two seem to be involved in co-factor biosynthesis, and the remaining two, including viperin, have unknown enzymatic activities (23). The human enzyme is a 361-residue protein that comprises three distinct domains: an N-terminal amphipathic helix thought to play a role in localizing viperin to the endoplasmic reticulum and lipid droplets (19); a large, central domain that contains four motifs characteristic of radical SAM enzymes; and a conserved C-terminal domain that may be involved in [Fe 4 S 4 ] cluster assembly, the proper folding of viperin, and/or substrate recognition (20,24).…”

Theory and Application of the Relationship Between Steady-State Isotope Effects on Enzyme Intermediate Concentrations and Net Rate Constants

“…Radical SAM enzymes are characterized by an active site [4Fe-4S] 1+ cluster that serves to reductively homolyze S- adenosyl-L-methionine (SAM) to produce L-methionine and a 5′-deoxyadenosyl radical (Frey and Magnusson, 2003; Wang and Frey, 2007; Duschene et al, 2009; Frey, 2014). The 5′-deoxyadenosyl radical can then act as a radical initiator for a broad range chemical reactions catalyzed by this enzyme superfamily (Broderick et al, 2014; Frey, 2014; Mehta et al, 2015; Landgraf et al, 2016). …”

Mammalian Fe–S proteins: definition of a consensus motif recognized by the co-chaperone HSC20

“…The cytosolic isoform of aconitase is a bifunctional enzyme (iron regulatory protein 1, IRP1/ cytosolic aconitase, ACO1), involved in regulation of cellular iron homeostasis 13–15 . Moreover, an astonishing array of diverse and biochemically challenging reactions is catalyzed by the radical S-adenosylmethionine (SAM) enzymes, which are involved in thermodynamically unfavorable reactions and require redox-active [Fe4–S4] conserved clusters for activity 16 . Several nucleic acid processing enzymes, such as DNA polymerases, glycosylases, helicases and primases require Fe-S clusters for their function 17 .…”

“…Sophisticated bioinformatics tools were applied to the radical S-adenosylmethionine (SAM) superfamily to overcome the obstacles in the analysis of such a large number of enzymes which link different biosynthetic pathways. Radical SAM enzymes contain [Fe4-S4] cluster cofactors and are involved in an astonishing array of reactions that impact numerous cellular processes, including transcription, translation, gene regulation, the biosynthesis of several essential metabolites and complex metallo-cofactors, and signal transduction 16, 27, 28 . The term radical SAM was coined in a powerful bioinformatics approach, which used iterative profile methods to identify high homology and distinguishing features among the five founding members of the superfamily (biotin synthase, lipoyl synthase, lysine 2,3-aminomutase, and the activases for pyruvate-formate lyase and class III ribonucleotide reductases) and over 600 other uncharacterized proteins 29 .…”