An essential developmental function for murine phosphoglycolate phosphatase in safeguarding cell proliferation

Segerer, Gabriela; Hadamek, Kerstin; Zundler, Matthias; Fekete, Ágnes; Seifried, Annegrit; Mueller, Martin J.; Köentgen, Frank; Gessler, Manfred; Jeanclos, Elisabeth; Gohla, Antje

doi:10.1038/srep35160

Cited by 24 publications

(29 citation statements)

References 54 publications

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“…Because of the detrimental effect of these metabolites, it becomes essential to clear the cell of these metabolic toxins. This is reflected by the fact that phosphoglycolate phosphatase is an essential gene in the mouse (21). Also, in Arabidopsis, knockout of PGLP1 isoform leads to impaired post-germination development of primary leaves (22).…”

Section: P Berghei Phosphoglycolate Phosphatasementioning

confidence: 99%

Phosphoglycolate phosphatase is a metabolic proofreading enzyme essential for cellular function in Plasmodium berghei

Nagappa¹,

Satha

Govindaraju

et al. 2019

Journal of Biological Chemistry

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Edited by Ruma BanerjeePlasmodium falciparum (Pf) 4-nitrophenylphosphatase has been shown previously to be involved in vitamin B1 metabolism. Here, conducting a BLASTp search, we found that 4-nitrophenylphosphatase from Pf has significant homology with phosphoglycolate phosphatase (PGP) from mouse, human, and yeast, prompting us to reinvestigate the biochemical properties of the Plasmodium enzyme. Because the recombinant PfPGP enzyme is insoluble, we performed an extended substrate screen and extensive biochemical characterization of the recombinantly expressed and purified homolog from Plasmodium berghei (Pb), leading to the identification of 2-phosphoglycolate and 2-phospho-L-lactate as the relevant physiological substrates of PbPGP. 2-Phosphoglycolate is generated during repair of damaged DNA ends, 2-phospho-L-lactate is a product of pyruvate kinase side reaction, and both potently inhibit two key glycolytic enzymes, triosephosphate isomerase and phosphofructokinase. Hence, PGP-mediated clearance of these toxic metabolites is vital for cell survival and functioning. Our results differ significantly from those in a previous study, wherein the PfPGP enzyme has been inferred to act on 2-phospho-D-lactate and not on the L isomer. Apart from resolving the substrate specificity conflict through direct in vitro enzyme assays, we conducted PGP gene knockout studies in P. berghei, confirming that this conserved metabolic proofreading enzyme is essential in Plasmodium. In summary, our findings establish PbPGP as an essential enzyme for normal physiological function in P. berghei and suggest that drugs that spe-cifically inhibit Plasmodium PGP may hold promise for use in anti-malarial therapies.The haloacid dehalogenase superfamily (HADSF) 5 is a large family of enzymes consisting mainly of phosphatases and phosphotransferases, which are both intracellular and extracellular in nature. These enzymes are characterized by the presence of a core Rossmanoid fold and a cap domain (1, 2). Studies of HADSF members have focused on identifying their physiological substrates by screening a wide range of metabolites that include sugar phosphates, lipid phosphates, nucleotides, as well as phosphorylated amino acids and co-factors. This approach has helped us understand the physiological relevance of these enzymes in various cellular processes, such as cell wall synthesis, catabolic and anabolic pathways, salvage pathways, signaling pathways, and detoxification (3-13). Apart from dephosphorylating metabolites, HADSF members have also been known to dephosphorylate proteins, and such members are characterized by the absence of the cap domain (1, 2). A largescale study reported by Huang et al. (5) has identified a HADSF member from Salmonella enterica that catalyzes dephosphorylation of more than 100 phosphorylated substrates (5). This extended substrate specificity is a common observation in HADSF members and often leads to a confounding situation where determining the physiological substrate of such promiscuous enzymes becomes a chall...

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Section: P Berghei Phosphoglycolate Phosphatasementioning

confidence: 99%

Phosphoglycolate phosphatase is a metabolic proofreading enzyme essential for cellular function in Plasmodium berghei

Nagappa¹,

Satha

Govindaraju

et al. 2019

Journal of Biological Chemistry

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“…Due to the detrimental effect of these metabolites, it becomes essential to clear the cell of these metabolic toxins. This is reflected upon by the fact that phosphoglycolate phosphatase is an essential gene in mouse [25]. Also, in Arabidopsis, knockout of PGLP1 isoform leads to impaired post-germination development of primary leaves [26].…”

Section: Discussionmentioning

confidence: 99%

Metabolic proof-reading in Plasmodium berghei: essentiality of phosphoglycolate phosphatase

Nagappa

Satha

Govindaraju

et al. 2018

Preprint

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12Plasmodium falciparum (Pf) 13 4-nitrophenylphosphatase was earlier shown to be 14 involved in vitamin B1 metabolism by Knöckel et 15 al., (Mol. Biochem. Parasitol. 2008, 157, 241-16 243). An independent BLASTp search showed that 17 the protein had significant homology with phos-18 phoglycolate phosphatase from mouse, human and 19 yeast, and prompted us to re-investigate the bio-20 chemical properties of the recombinant Plasmod-21 ium enzyme. Owing to the insoluble nature of 22 the Pf enzyme, an extended substrate screen and 23 biochemical characterization was performed on its 24 P. berghei (Pb) homolog that led to the identi-25 fication of 2-phosphoglycolate and 2-phospho L-26 lactate as the relevant physiological substrates. 2-27 phosphoglycolate is known to be generated during 28 repair of damaged DNA ends whereas, 2-phospho 29 L-lactate is a product of pyruvate kinase side reac-30 tion. These metabolites are potent inhibitors of the 31key glycolytic enzymes, triosephosphate isomerase 32 and phosphofructokinase, and hence clearance of 33 these toxic metabolites is vital for cell survival and 34 functioning. Gene knockout studies conducted in 35 P. berghei revealed the essential nature of this con-36 served 'metabolic proof-reading enzyme'. 37 Haloacid dehalogenase superfamily 38 (HADSF) is a large family of enzymes consisting 39 mainly of phosphatases and phosphotransferases, 40 that are both intracellular and extracellular in na-41 ture. These enzymes are characterized by the pres-42 ence of a core Rossmanoid-fold and a cap-domain 43 (1, 2). Studies on HADSF members have focused 44 on identifying their physiological substrates by 45 screening a wide range of metabolites that include 46 sugar phosphates, lipid phosphates, nucleotides as 47 well as phosphorylated amino acids and co-factors. 48 This approach has helped understand the physiolog-49 ical relevance of these enzymes in various cellular 50 processes such as cell wall synthesis, catabolic and 51 anabolic pathways, salvage pathways, signaling 52 pathways and detoxification (3-13). Apart from 53 dephosphorylating metabolites, HADSF members 54 have also been know to dephosphorylate proteins 55 and such members are characterized by the absence 56 of the cap domain (1, 2). A large scale study re-57 ported by Huang et al., has identified a HADSF 58 member from Salmonella enterica that catalyzes 59 dephosphorylation of more than 100 phosphory-60 lated substrates (5). This extended substrate speci-61 ficity is a common observation in HADSF members 62 and often leads to a confounding situation where 63 determining the physiological substrate of such 64 promiscuous enzymes becomes a challenging task. 65 Recent studies have identified and char-66 acterised HADSF members from the apicom-67 plexan parasite, Plasmodium (4, 10, 13-16). 68 HADSF members from Plasmodium have been 69 1 P. berghei phosphoglycolate phosphatase found to be involved in processes that lead to 70 the development of resistance to the drug fos-71 midomycin, which inhibits isoprenoid biosynthe-...

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“…Studies have shown that PGP inactivation attenuated triosephosphate isomerase activity, increased triglyceride levels at the expense of the cellular phosphatidylcholine content, and inhibited cell proliferation [38,39]. These effects were prevented under hypoxic conditions or by blocking phosphoglycolate release from damaged DNA.…”

Section: Improving Pi Absorption Capacity By Changing Root Structure mentioning

confidence: 99%

Identification of phosphorus stress related proteins in the seedlings of Dongxiang wild rice (Oryza rufipogon Griff.) using label-free quantitative proteomic analysis

Deng¹,

Bai²,

Dai³

et al. 2020

Preprint

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Background: The lack of available phosphorus (P) in soil is one of the important factors restricting rice growth. Previous studies indicated that Dongxiang wild rice (DXWR, O. rufipogon Griff.) was resistant to low-P stress. So far, the research of resistance mechanism in DXWR was very limited.Results: The results showed that 3589 significant differential accumulation proteins were identified between low P and the normal P treated root samples. 60 up-regulated and 15 down-regulated proteins were identified with ≥ 1.5-fold changes as an additional standard. Furthermore, among 75 significantly different expression proteins (SDEPs), 24 proteins also detected in previous transcriptome dataset verified by qRT-PCR, including OsPT2, OsPT8, OsPAP10c, OsPAP10a and OsPHF1. Through comprehensive analysis, it was found that DXWR could increase PAPs, membrane location of PTs, rhizosphere area, alternative splicing and decrease ROS activity to deal with low-P stress. Moreover, among the genes corresponding to 75 SDEPs, 7 uncharacterized genes were located in previous P related QTL intervals, of which two genes (LOC_Os12g09620 and LOC_Os03g40670) have been detected at both transcriptome and proteome levels. In addition, the expression patterns of OsPHR1, OsPHR2, OsPHO1 and NAT-OsPHO1 in DXWR were different in cultivated rice, suggesting that the response mechanism of some low-P tolerance in DXWR might be different from that in cultivated rice.Conclusions: This study screened out some candidate genes for low-P resistance and preliminarily verified that there might be a different low-P response mechanism in DXWR than in cultivated rice, which would provide insights in cloning the P-deficiency genes from wild rice, as well as elucidating the molecular mechanism of low-P resistance in DXWR.

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An essential developmental function for murine phosphoglycolate phosphatase in safeguarding cell proliferation

Cited by 24 publications

References 54 publications

Phosphoglycolate phosphatase is a metabolic proofreading enzyme essential for cellular function in Plasmodium berghei

Phosphoglycolate phosphatase is a metabolic proofreading enzyme essential for cellular function in Plasmodium berghei

Metabolic proof-reading in Plasmodium berghei: essentiality of phosphoglycolate phosphatase

Identification of phosphorus stress related proteins in the seedlings of Dongxiang wild rice (Oryza rufipogon Griff.) using label-free quantitative proteomic analysis

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