Biosynthesis of nucleic acid purines. II. Role of hypoxanthine and xanthine compounds

Abrams, Richard; Bentley, Marian

doi:10.1016/0003-9861(55)90098-9

Cited by 39 publications

(11 citation statements)

References 10 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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“…166 observations directed our attention to the metabolic fate of IMP. The initial reaction of the guanine nucleotide branch, the oxidation of IMP to XMP, with concomitant reduction of NAD+, is catalysed by IMP dehydrogenase (EC 1.2.1.14) (Magasanik et al, 1957;Abrams & Bentley, 1955;Lagerkvist, 1958). This enzyme has been assayed previously in several mammalian tissues, and examined in some detail in mouse sarcoma 180 cells (Anderson & Sartorelli, 1968) and human placenta (Holmes et al, 1974).…”

mentioning

confidence: 99%

Partial purification, properties and regulation of inosine 5′-phosphate dehydrogenase in normal and malignant rat tissues

Jackson¹,

Morris²,

Weber³

1977

Biochemical Journal

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IMP dehydrogenase (EC 1.2.1.14) was purified 180-fold from rat liver and from the transplantable rat hepatoma 3924A. The enzymes from the two sources were apparently identical; they exhibited hyperbolic saturation kinetics and an ordered, sequential mechanism, and were subject to inhibition by a number of purine nucleotides. Km values for the substrates, IMP and NAD+, were 12 and 24pUM respectively. IMP dehydrogenase activity in a spectrum of rat hepatomas was increased, relative to normal liver, by 2.5-13-fold; these increases correlated with tumour growth rate. Activity in two rat kidney tumours was increased 3-fold relative to that in normal renal cortex; control of activity of this enzyme is apparently altered in neoplastic cells. After partial hepatectomy, IMP dehydrogenase activity began to rise 6h after operation, reaching a peak of580 % ofnormal activity by 18h. Activity in neonatal liver, however, was only slightly higher than that in the adult. Organ-distribution studies showed highest enzyme activities in spleen and thymus. In livers of rats starved for 3 days, where all enzymes, except those involved in gluconeogenesis, showed decreased activity, IMP dehydrogenase activity was increased; this change was accompanied by a rise in hepatic GTP concentrations. It is concluded that IMP dehydrogenase is a key enzyme in the regulation of GTP production, and thus involved in regulation ofnucleic acid biosynthesis. The increased activity ofIMP dehydrogenase in liver of starved rats may be related to the requirement for GTP for gluconeogenesis.

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“…The infrared spertrum (0.96 mg. in 250-mg. potassium bromide pellet) was identical with that of the authentic compound with absorption ( p ) at 5.75 (s), 6.15 (s), 6 Very slow crystallization from ethanol frequently yields the derivative as dense opaque yellow spherules with significant differences in the infrared, particularly in the 10-11-p region.…”

Section: Isolation Of 24-dinitrophenyl( + )S-methyl-bcysteine Sulj-mentioning

confidence: 72%

“…6 In view of the relative inaccessability of the original, details are given. This was prepared essentially according to Pan and coworkers.…”

Section: P-[nn-bis(8-chloroethyl)amino] Benzoic Acid (Vi)mentioning

confidence: 99%

Isolation of (+)S-Methyl-L-cysteine Sulfoxide and of (+)S-n-Propyl-L-cysteine Sulfoxide from Onions as their N-2,4-Dinitrophenyl Derivatives

Carson¹,

Wong²

1961

J. Org. Chem.

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Biosynthesis of nucleic acid purines. II. Role of hypoxanthine and xanthine compounds

Cited by 39 publications

References 10 publications

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

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

Partial purification, properties and regulation of inosine 5′-phosphate dehydrogenase in normal and malignant rat tissues

Isolation of (+)S-Methyl-L-cysteine Sulfoxide and of (+)S-n-Propyl-L-cysteine Sulfoxide from Onions as their N-2,4-Dinitrophenyl Derivatives

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