Biosynthesis of nucleic acid purines. I. Formation of guanine from adenine compounds in bone marrow extracts

Abrams, Richard; Bentley, Marian

doi:10.1016/0003-9861(55)90347-7

Cited by 35 publications

(8 citation statements)

References 11 publications

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“…In 1955, IMPDH was first described in the investigation of purine biosynthesis as a NAD + requiring dehydrogenase necessary to convert inosine monophosphate (IMP) to xanthosine monophosphate (XMP) in rabbit bone marrow extracts [16,17] and pigeon liver extracts [18]. IMPDH is the rate-limiting step in de novo biosynthesis of guanine nucleotides (Figure 2).…”

Section: Mpa Inhibits Impdh Activity and Possesses An Immunosupprementioning

confidence: 99%

Anti-Tumor Potential of IMP Dehydrogenase Inhibitors: A Century-Long Story

Naffouje

Grover

et al. 2019

Cancers

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The purine nucleotides ATP and GTP are essential precursors to DNA and RNA synthesis and fundamental for energy metabolism. Although de novo purine nucleotide biosynthesis is increased in highly proliferating cells, such as malignant tumors, it is not clear if this is merely a secondary manifestation of increased cell proliferation. Suggestive of a direct causative effect includes evidence that, in some cancer types, the rate-limiting enzyme in de novo GTP biosynthesis, inosine monophosphate dehydrogenase (IMPDH), is upregulated and that the IMPDH inhibitor, mycophenolic acid (MPA), possesses anti-tumor activity. However, historically, enthusiasm for employing IMPDH inhibitors in cancer treatment has been mitigated by their adverse effects at high treatment doses and variable response. Recent advances in our understanding of the mechanistic role of IMPDH in tumorigenesis and cancer progression, as well as the development of IMPDH inhibitors with selective actions on GTP synthesis, have prompted a reappraisal of targeting this enzyme for anti-cancer treatment. In this review, we summarize the history of IMPDH inhibitors, the development of new inhibitors as anti-cancer drugs, and future directions and strategies to overcome existing challenges.

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Section: Mpa Inhibits Impdh Activity and Possesses An Immunosupprementioning

confidence: 99%

Anti-Tumor Potential of IMP Dehydrogenase Inhibitors: A Century-Long Story

Naffouje

Grover

et al. 2019

Cancers

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“…As soon as xanthine was removed, the elution system was changed so as to provide an acid gradient for the remainder of the process. This technique is a modification of the stepwise elution procedure described by Abrams and Bentley (21) and Wall (22).3 A double reservoir was put in place in which the upper flask, a three-liter separatory funnel, containing 2.2 L. of 2.67 N HCl, was arranged to feed into the lower flask, a two-liter bottle with an outlet near its base, containing 2.0 L. of 0.15 N HCl, as the contents of the latter flowed on the column. Mixing was effected within the lower chamber by means of a magnetic stirrer, and the rate of elution was maintained at about 3 ml.…”

Section: Methodsmentioning

confidence: 99%

On the Mechanism of Overproduction of Uric Acid in Patients With Primary Gout1

Wyngaarden¹,

Blair²,

Hilley³

1958

J. Clin. Invest.

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In order to study the rate of generation of uric acid in man, Benedict, Roche, Yu, Bien, Gutman, and Stetten (5-7) administered relatively large doses of glycine-N15 orally to control and gouty subjects and measured the appearance of isotope in urinary uric acid. With this technique, they demonstrated overincorporation of isotope into uric acid only in gouty subjects excreting large quantities of uric acid in urine. Subsequently, however, excessive incorporation of tracer quantities of glycine-1-C14 into uric acid was demonstrated in all of seven subjects studied, regard-

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“…IMPDH2 is the rate-limiting enzyme in the production of GTP [62][63][64] . Because EZH2 regulated IMPDH2 tetramerization and activity (Figures 3M and 3N), we checked the contribution of EZH2 to cellular GTP production in melanoma.…”

Section: Gtpmentioning

confidence: 99%

Cytosolic EZH2-IMPDH2 complex regulates melanoma progression and metastasis via GTP regulation

Abali

Noguchi

Szeto

et al. 2021

Preprint

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The enhancer of zeste homolog 2 (EZH2) oncoprotein is a histone methyltransferase that functions canonically as a catalytic subunit of the polycomb repressive complex 2 (PRC2) to tri-methylate histone H3 at Lys 27 (H3K27me3). Although targeting EZH2 methyltransferase is a promising therapeutic strategy against cancer, methyltransferase-independent oncogenic functions of EZH2 are described. Moreover, pharmacological EZH2 methyltransferase inhibition was only variably effective in pre-clinical and clinical studies, suggesting that targeting EZH2 methyltransferase alone may be insufficient. Here, we demonstrate a non-canonical mechanism of EZH2’s oncogenic activity characterized by interactions with inosine monophosphate dehydrogenase 2 (IMPDH2) and downstream promotion of guanosine-5’-triphosphate (GTP) production. EZH2-IMPDH2 interactions identified by Liquid Chromatography-Mass Spectrometry (LC-MS) of EZH2 immunoprecipitates from melanoma cells were verified to occur between the N-terminal EED-binding domain of cytosolic EZH2 and the CBS domain of IMPDH2 in a methyltransfersase-independent manner. EZH2 silencing reduced cellular GTP, ribosome biogenesis, RhoA-mediated actomyosin contractility and melanoma cell proliferation and invasion by impeding the activity of IMPDH2. Guanosine, which replenishes GTP, reversed these effects and thereby promoted invasive and clonogenic cell states even in EZH2 silenced cells. IMPDH2 silencing antagonized the proliferative and invasive effects of EZH2, also in a guanosine-reversible manner. In human melanomas, high cytosolic EZH2 and IMPDH2 expression were associated with nucleolar enlargement, a marker of ribosome biogenesis. EZH2-IMPDH2 complexes were also observed in a range of cancers in which Sappanone A (SA), which inhibits EZH2-IMPDH2 interactions, was anti-tumorigenic, although notably non-toxic in normal cells. These findings illuminate a previously unrecognized, non-canonical, methyltransferase-independent, and GTP-dependent mechanism by which EZH2 regulates tumorigenicity in melanoma and other cancers, opening new avenues for development of anti-EZH2 therapeutics. Graphical AbstractHighlightsEZH2 has non-canonical methyltransferase-independent and GTP-dependent tumorigenic and metastatic functions in melanoma.The N-terminal EED-binding domain of EZH2 interacts with the CBS domain of IMPDH2 in a polycomb repressive complex 2- (PRC2-) and methylation-independent manner.EZH2 accumulates with IMPDH2 in the cytoplasm and increases IMPDH2’s tetramerization-mediated activity independently of EZH2 methyltransferase.EZH2 upregulates GTP synthesis by IMPDH2 activation and thereby activates ribosome biogenesis via rRNA synthesis and actomyosin contractility via RhoA GTPase.Sappanone A (SA) inhibits IMPDH2-EZH2 interactions and is anti-proliferative across a range of cancers including melanoma, but not in normal cells.

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Biosynthesis of nucleic acid purines. I. Formation of guanine from adenine compounds in bone marrow extracts

Cited by 35 publications

References 11 publications

Anti-Tumor Potential of IMP Dehydrogenase Inhibitors: A Century-Long Story

Anti-Tumor Potential of IMP Dehydrogenase Inhibitors: A Century-Long Story

On the Mechanism of Overproduction of Uric Acid in Patients With Primary Gout1

Cytosolic EZH2-IMPDH2 complex regulates melanoma progression and metastasis via GTP regulation

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