A highly specific phosphatase that acts on ADP-ribose 1''-phosphate, a metabolite of tRNA splicing in Saccharomyces cerevisiae

Shull, Neil P.; Spinelli, Sherry L.; Phizicky, Eric M.

doi:10.1093/nar/gki211

Cited by 58 publications

(64 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Conserved among all living organisms, NAD ϩ -dependent histone deacetylases produce OAADPr as a product (3,5), which can be readily converted to ADPr by cellular esterases (24). Another source of ADPr in yeast is the dephosphorylation of ADP-ribose 1Љ-phosphate, a product of NAD ϩ -dependent tRNA splicing (57,58). Other potential sources of ADPr in yeast remain to be identified.…”

Section: Discussionmentioning

confidence: 99%

Hydrolase Regulates NAD+ Metabolites and Modulates Cellular Redox

Tong

Lee

Denu

2009

Journal of Biological Chemistry

View full text Add to dashboard Cite

Although the classical redox functions of co-enzyme NAD ؉ are firmly established in metabolism, there are numerous enzymes that catalyze cleavage of NAD ؉ to yield free ADP-ribose (ADPr) or related metabolites, whose functions remain largely unknown. Here we show that the Nudix (nucleoside diphosphate linked to another moiety X) hydrolase Ysa1 from Saccharomyces cerevisiae is a major regulator of cellular ADPr and O-acetyl-ADP-ribose (OAADPr). OAADPr is the direct product of NAD ؉ -dependent protein deacetylases (sirtuins) and is readily converted to ADPr. Ysa1 cleaves ADPr/OAADPr into ribose phosphate/acetyl-ribose phosphate and AMP. In cells lacking Ysa1 (⌬ysa1), ADPr and OAADPr levels increased ϳ50%, with a corresponding decrease in AMP. Strikingly, ⌬ysa1 cells display higher resistance to exogenous reactive oxygen species (ROS) and 40% lower basal levels of endogenous ROS, compared with wild type. The biochemical basis for these differences in ROS-related phenotypes was investigated, and the results provide evidence that increased ADPr/OAADPr levels protect cells via the following two pathways: (i) lower ROS production through inhibition of complex I of the mitochondrial electron transport chain, and (ii) generation of higher levels of NADPH to suppress ROS damage. The latter occurs through diverting glucose into the pentose phosphate pathway by ADPr inhibition of glyceraldehyde-3-phosphate dehydrogenase, a central enzyme of glycolysis. NADϩ is well known for its role as a hydride-transferring co-enzyme in many oxidation-reduction reactions of metabolism. However, NAD ϩ is also a substrate for NAD ϩ glycohydrolases, ADP-ribose transferases, poly(ADP-ribose) polymerases (PARPs), 2 cyclic ADP-ribose synthases (1, 2), and sirtuins (3, 4), all of which cleave the glycosidic bond of NAD ϩ to produce nicotinamide and an ADP-ribosyl product. Notably, sirtuins catalyze NAD ϩ -dependent lysine deacetylation to generate nicotinamide, deacetylated lysine, and OAADPr (5, 6).OAADPr has been proposed to act as a second messenger, signaling to other processes that NAD ϩ -dependent protein deacetylation has occurred (7-9). The biological functions and in vivo metabolism of OAADPr and free ADPr are largely unknown.Through a quantitative microinjection assay of starfish oocytes, both ADPr and OAADPr caused a delay/block in oocyte maturation, suggesting ADPr/OAADPr may have specific biological activity (10). In mammalian cells, intracellular ADPr/OAADPr can activate the TRPM2 (transient receptor melastatin-related ion channel 2) nonselective cationic channel (11-13). TRPM2 contains a conserved intracellular Nudix hydrolase domain (referred to as NudT9H) that directly binds ADPr/OAADPr, but it is incapable of cleaving the ligand because a major catalytic residue is missing (11,14). Although still disputed, ADPr binding to NudT9H appears to be required for the well known oxidative stress activation of the channel (13, 15). Cell stress via puromycin treatment led to TRPM2-mediated cell death that was dependent on sirtuin deacetyl...

show abstract

Section: Discussionmentioning

confidence: 99%

Hydrolase Regulates NAD+ Metabolites and Modulates Cellular Redox

Tong

Lee

Denu

2009

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…However, this assignment is controversial. A nuclear Appr-10-pase (Poa1p in yeast, [20]) is an enzyme of a tRNA metabolic pathway, but there is no evidence for coronavirus Nsp3 ever being translocated to the nucleus, and the other enzymes involved in this pathway are missing in coronaviruses (with the exception of the cyclic 10,20-phosphodiesterase (CPDase) in group 2a viruses such as Mouse Hepatitis Virus, Bovine Coronavirus, and Human Coronavirus OC43). Therefore, it has been proposed that the Xdomain may be involved in binding poly(ADP-ribose), a metabolic product of NAD + synthesized by the enzyme poly(ADP-ribose) polymerase (PARP; [23]).…”

Section: Discussionmentioning

confidence: 99%

The SARS-Unique Domain (SUD) of SARS Coronavirus Contains Two Macrodomains That Bind G-Quadruplexes

Tan¹,

Hilgenfeld²

2009

SciVee

View full text Add to dashboard Cite

Since the outbreak of severe acute respiratory syndrome (SARS) in 2003, the three-dimensional structures of several of the replicase/transcriptase components of SARS coronavirus (SARS-CoV), the non-structural proteins (Nsps), have been determined. However, within the large Nsp3 (1922 amino-acid residues), the structure and function of the so-called SARSunique domain (SUD) have remained elusive. SUD occurs only in SARS-CoV and the highly related viruses found in certain bats, but is absent from all other coronaviruses. Therefore, it has been speculated that it may be involved in the extreme pathogenicity of SARS-CoV, compared to other coronaviruses, most of which cause only mild infections in humans. In order to help elucidate the function of the SUD, we have determined crystal structures of fragment 389-652 (''SUD core '') of Nsp3, which comprises 264 of the 338 residues of the domain. Both the monoclinic and triclinic crystal forms (2.2 and 2.8 Å resolution, respectively) revealed that SUD core forms a homodimer. Each monomer consists of two subdomains, SUD-N and SUD-M, with a macrodomain fold similar to the SARS-CoV X-domain. However, in contrast to the latter, SUD fails to bind ADP-ribose, as determined by zone-interference gel electrophoresis. Instead, the entire SUD core as well as its individual subdomains interact with oligonucleotides known to form G-quadruplexes. This includes oligodeoxy-as well as oligoribonucleotides. Mutations of selected lysine residues on the surface of the SUD-N subdomain lead to reduction of Gquadruplex binding, whereas mutations in the SUD-M subdomain abolish it. As there is no evidence for Nsp3 entering the nucleus of the host cell, the SARS-CoV genomic RNA or host-cell mRNA containing long G-stretches may be targets of SUD. The SARS-CoV genome is devoid of G-stretches longer than 5-6 nucleotides, but more extended G-stretches are found in the 39-nontranslated regions of mRNAs coding for certain host-cell proteins involved in apoptosis or signal transduction, and have been shown to bind to SUD in vitro. Therefore, SUD may be involved in controlling the host cell's response to the viral infection. Possible interference with poly(ADP-ribose) polymerase-like domains is also discussed.

show abstract

“…In eukaryotes, major sources of ADP-ribose are (i) poly(ADP-ribose) degradation by nuclear and mitochondrial glycohydrolases (though not in yeast) [201,202], (ii) the dephosphorylation of ADP-ribose 1''-phosphate, a product of NAD + -dependent tRNA splicing [203], (iii) cell surface and mitochondrial NAD glycohydrolases (ADP-ribosyl cyclases) [204,205] and (iv) the deacetylation of O-acetyl-ADP-ribose, a product of the Sir2 family of NAD + -dependent histone deacetylases [206]. Of these, the rapid turnover of nuclear poly(ADP-ribose) synthesised in response to cellular stress could lead to a very large increase in free ADP-ribose, the intracellular concentration of which has been estimated at 44-73 µM in mouse and human T cells [207] but at only 0.5 µM in anucleate human erythrocytes [208].…”

Section: Human and Mouse Nudix Hydrolasesmentioning

confidence: 99%

“…Experiments with PARP inhibitors suggest that PARP-related NAD glycohydrolase activities could give rise to this ADP-ribose [217,219,220]. ADP-ribose also inhibits ATP-sensitive K + channels in myocytes [221] and may have further regulatory roles through its interaction with macro domains, structural modules found in a wide variety of proteins that bind ADP-ribose and its derivatives with high affinity [203,222,223]. The 52-kDa human NUDT12 protein is 59% identical to E. coli YjaD over a 60-amino-acid region encompassing the Nudix motif and, like Yjad, hydrolyses NADH and NADPH with 20-fold greater efficiency than NAD + [224].…”

Section: Human and Mouse Nudix Hydrolasesmentioning

confidence: 99%

The Nudix hydrolase superfamily

McLennan

2005

Cell. Mol. Life Sci.

526

544

View full text Add to dashboard Cite

Nudix hydrolases are found in all classes of organism and hydrolyse a wide range of organic pyrophosphates, including nucleoside di- and triphosphates, dinucleoside and diphosphoinositol polyphosphates, nucleotide sugars and RNA caps, with varying degrees of substrate specificity. Some superfamily members, such as Escherichia coli MicrotT, have the ability to degrade potentially mutagenic, oxidised nucleotides while others control the levels of metabolic intermediates and signalling compounds. In prokaryotes and simple eukaryo tes, the number of Nudix genes varies from 0 to over 30, reflecting the metabolic complexity and adaptability of the organism. Mammals have around 24 Nudix genes, several of which encode more than one variant. This review integrates the sizeable recent literature on these proteins with information from global functional genomic studies to provide some insights into the possible roles of different superfamily members in cellular metabolism and homeostasis and to stimulate discussion and further research into this ubiquitous protein family.

show abstract

A highly specific phosphatase that acts on ADP-ribose 1''-phosphate, a metabolite of tRNA splicing in Saccharomyces cerevisiae

Cited by 58 publications

References 45 publications

Hydrolase Regulates NAD+ Metabolites and Modulates Cellular Redox

Hydrolase Regulates NAD+ Metabolites and Modulates Cellular Redox

The SARS-Unique Domain (SUD) of SARS Coronavirus Contains Two Macrodomains That Bind G-Quadruplexes

The Nudix hydrolase superfamily

Contact Info

Product

Resources

About