Regulation of inosine monophosphate dehydrogenase type I and type II isoforms in human lymphocytes

Jain, Jugnu; Almquist, Susan J.; Ford, Pamella J.; Shlyakhter, Dina; Wang, Yongping; Nimmesgern, Elmar; Germann, Ursula A.

doi:10.1016/j.bcp.2003.09.043

Cited by 74 publications

(67 citation statements)

References 26 publications

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“…However, it must be noted that MPA inhibits both IMPDH-I and -II isoforms, 36 and the IMPDH activity assay reported in this article also measures the activity of both IMPDH-I and -II. Although the data on IMPDH II protein expression in patients with diabetes are preliminary, it may suggest that diabetes not only affects IMPDH activity, but may to some extent also alter the expression of key enzymes that define this aspect of immune response.…”

Section: Discussionmentioning

confidence: 99%

Effect of Diabetes Mellitus on Mycophenolate Sodium Pharmacokinetics and Inosine Monophosphate Dehydrogenase Activity in Stable Kidney Transplant Recipients

Patel¹,

Richman²,

Yang³

et al. 2007

Therapeutic Drug Monitoring

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Effect of diabetes mellitus on mycophenolic acid (MPA) pharmacokinetics and catalytic activity of inosine monophosphate dehydrogenase (IMPDH) was investigated in maintenance kidney transplant recipients. Demographically matched diabetic (n = 9) and nondiabetic (n = 9) patients were included in a 12-hour open-label, steady-state study after oral administration of entericcoated mycophenolate sodium. Concentrations of total MPA and free MPA, MPA-glucuronide, and acyl-MPA-glucuronide were measured and oral acetaminophen absorption was used as a marker for gastric-emptying rate. Median (range) of MPA area under the curve 0-12 was 36.7 (range, 16.4-116.4) mg * h/L in diabetic and 48.2 (range, 34.9-80.1) mg * h/L in nondiabetic patients (P = 0.49). All other primary pharmacokinetic parameters, including time to maximum concentration, for total or unbound MPA as well as MPA metabolites were comparable. In contrast, IMPDH activity was 17.5 ± 2.8 versus 46.6 ± 2.5 nmol XMP/h/mg protein in diabetics and nondiabetics, respectively (P < 0.0001) and was significantly lower in the diabetics irrespective of concomitant therapy with cyclosporine or tacrolimus. This study demonstrated that diabetes does not alter MPA pharmacokinetics when administered as enteric-coated mycophenolate sodium; however, IMPDH activity appeared to be significantly lower in patients with diabetes independent of the unbound or total concentrations of MPA. Further investigations are warranted to investigate the regulation of IMPDH enzyme in patients with diabetes.

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Section: Discussionmentioning

confidence: 99%

Effect of Diabetes Mellitus on Mycophenolate Sodium Pharmacokinetics and Inosine Monophosphate Dehydrogenase Activity in Stable Kidney Transplant Recipients

Patel¹,

Richman²,

Yang³

et al. 2007

Therapeutic Drug Monitoring

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“…AVN-944 is an inhibitor of human IMPDH [19] and also displays antiproliferative activity [20]. The cyano-substituted compound VX-148 (4) displays promising immunosuppressive activity [21]. Application of isosteres of the urea linker of VX-497 is a point of concern.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and antiviral activity of a novel class of (5-oxazolyl)phenyl amines

Zhong

Zhang

Peng

et al. 2013

European Journal of Medicinal Chemistry

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“…Mammals have two IMPDH genes, encoding IMPDH1 and IMPDH2, and most tissues express both isozymes (18,19). In contrast, only IMPDH1 appears to be expressed in the retina; in addition, retina contains distinct IMPDH1 isoforms generated by alternative mRNA splicing as follows: IMPDH1(546) (major) and IMPDH1(595) (minor) ( Fig.…”

Section: Imp Dehydrogenase (Impdh)mentioning

confidence: 99%

“…Others report that IMPDH binds DNA and may be involved in gene expression (16, 17). These observations suggest that IMPDH has a "moonlighting" function involving nucleic acid that is mediated by the subdomain.Mammals have two IMPDH genes, encoding IMPDH1 and IMPDH2, and most tissues express both isozymes (18,19). In contrast, only IMPDH1 appears to be expressed in the retina; in addition, retina contains distinct IMPDH1 isoforms generated by alternative mRNA splicing as follows: IMPDH1(546) (major) and IMPDH1(595) (minor) ( Fig.…”

mentioning

confidence: 99%

IMP Dehydrogenase Type 1 Associates with Polyribosomes Translating Rhodopsin mRNA

Mortimer

McGrew

et al. 2008

Journal of Biological Chemistry

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IMP dehydrogenase (IMPDH) catalyzes the pivotal step in guanine nucleotide biosynthesis. Here we show that both IMPDH type 1 (IMPDH1) and IMPDH type 2 are associated with polyribosomes, suggesting that these housekeeping proteins have an unanticipated role in translation regulation. This interaction is mediated by the subdomain, a region of disputed function that is the site of mutations that cause retinal degeneration. The retinal isoforms of IMPDH1 also associate with polyribosomes. The most common disease-causing mutation, D226N, disrupts the polyribosome association of at least one retinal IMPDH1 isoform. Finally, we find that IMPDH1 is associated with polyribosomes containing rhodopsin mRNA. Because any perturbation of rhodopsin expression can trigger apoptosis in photoreceptor cells, these observations suggest a likely pathological mechanism for IMPDH1-mediated hereditary blindness. We propose that IMPDH coordinates the translation of a set of mRNAs, perhaps by modulating localization or degradation. IMP dehydrogenase (IMPDH)2 catalyzes the reaction that controls the entry of purines into the guanine nucleotide pool, and thus controls proliferation (1). The enzyme is a homotetramer; each monomer is composed of a catalytic (␤/␣) 8 barrel and a subdomain containing two CBS domains (named for the related domain in cystathionine ␤-synthase) (Fig. 1). Deletion of the subdomain has no effect on enzymatic activity (2, 3), and the function of the subdomain in IMPDH is currently under debate. CBS domains act as adenosine nucleotide-binding modules in several proteins (4 -9), and a similar role has been proposed for the CBS domains of IMPDH (5), but we and others have been unable to confirm this function in IMPDH (10 -13). Notably, the CBS domains of IMPDH share little sequence identity with the other proteins, so it would not be surprising if their function has diverged. The subdomain does appear to coordinately regulate the adenine and guanine nucleotide pool in Escherichia coli, although the molecular mechanism of this process has not yet been elucidated (11). We have discovered that IMPDH binds single-stranded nucleic acids and that the subdomain mediates this interaction (10, 15). IMPDH associates with RNA in tissue culture cells, which suggests that this housekeeping enzyme is involved in translation, splicing, or some other feature of RNA metabolism (10, 15). Others report that IMPDH binds DNA and may be involved in gene expression (16, 17). These observations suggest that IMPDH has a "moonlighting" function involving nucleic acid that is mediated by the subdomain.Mammals have two IMPDH genes, encoding IMPDH1 and IMPDH2, and most tissues express both isozymes (18,19). In contrast, only IMPDH1 appears to be expressed in the retina; in addition, retina contains distinct IMPDH1 isoforms generated by alternative mRNA splicing as follows: IMPDH1(546) (major) and IMPDH1(595) (minor) ( Fig. 1; these proteins are also known as IMPDH1␣/IMPDH1(13b) and IMPDH␥/IMPDH1(Aϩ13b), respectively; the canonical enzyme is hereaft...

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Regulation of inosine monophosphate dehydrogenase type I and type II isoforms in human lymphocytes

Cited by 74 publications

References 26 publications

Effect of Diabetes Mellitus on Mycophenolate Sodium Pharmacokinetics and Inosine Monophosphate Dehydrogenase Activity in Stable Kidney Transplant Recipients

Effect of Diabetes Mellitus on Mycophenolate Sodium Pharmacokinetics and Inosine Monophosphate Dehydrogenase Activity in Stable Kidney Transplant Recipients

Synthesis and antiviral activity of a novel class of (5-oxazolyl)phenyl amines

IMP Dehydrogenase Type 1 Associates with Polyribosomes Translating Rhodopsin mRNA

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