Inosine-5′-monophosphate dehydrogenase explained

Inosine 5'-monophosphate dehydrogenase
Ec Number:1.1.1.205
Cas Number:9028-93-7
Go Code:0003938

Inosine 5′-monophosphate dehydrogenase (IMPDH) is a purine biosynthetic enzyme that catalyzes the nicotinamide adenine dinucleotide (NAD)-dependent oxidation of inosine monophosphate (IMP) to xanthosine monophosphate (XMP), the first committed and rate-limiting step towards the de novo biosynthesis of guanine nucleotides from IMP.[1] [2] IMPDH is a regulator of the intracellular guanine nucleotide pool, and is therefore important for DNA and RNA synthesis, signal transduction, energy transfer, glycoprotein synthesis, as well as other process that are involved in cellular proliferation.

Structure and function

The canonic monomeric form of IMPDH has a molecular masse of approximately 55 kDa[3] and generally consists of 400-500 residues.[4] IMPDHs have been described as tetrameric,[5] [6] [7] although further data validated the existence of octameric forms.[8] Most IMPDH monomers contain two domains: a catalytic (β/α)8 barrel domain with an active site located in the loops at the C-terminal end of the barrel, and a subdomain, named the Bateman domain, and consisting of two, repeated cystathionine beta synthetase (CBS) domains that are inserted within the dehydrogenase sequence.[4] [9] Monovalent cations have been shown to activate most IMPDH enzymes and may serve to stabilize the conformation of the active-site loop.[10]

The Bateman domain is not required for catalytic activity. Mutations within the Bateman domain or a complete deletion of the domain do not impair the in vitro catalytic activity of some IMPDH .[11] [12] [13] [14] Other deletion examples of the Bateman domain in IMPDH have shown an enhanced in vitro catalytic activity in comparison with the corresponding wild-type counterpart.[15] An in vivo deletion of the Bateman domain in E. coli suggests that the domain can act as a negative transregulator of adenine nucleotide synthesis.[16] [17] IMPDH has also been shown to bind nucleic acids,[18] [19] and this function can be impaired by mutations that are located in the Bateman domain.[20] The Bateman domain has also been implicated in mediating IMPDH association with polyribosomes,[21] which suggests a potential moonlighting role for IMPDH as a translational regulatory protein. In Staphylococcus aureus, IMPDH have been identified as a plasminogen-binding protein.[22] Drosophila IMPDH has been demonstrated to act as a sequence-specific transcriptional repressor that can reduce the expression of histone genes and E2F.[23] IMPDH localizes to the nucleus at the end of the S phase and nuclear accumulation is mostly restricted to the G2 phase. In addition, metabolic stress has been shown to induce the nuclear localization of IMPDH.

Mechanism

The overall reaction catalyzed by IMPDH is:[24]

\rightleftharpoons

xanthosine 5'-phosphate + NADH + H+

The mechanism of IMPDH involves a sequence of two different chemical reactions: (1) a fast redox reaction involving a hydride transfer to NAD which generates NADH and an enzyme-bound XMP intermediate (E-XMP*) and (2) a hydrolysis step that releases XMP from the enzyme. IMP binds to the active site and a conserved cysteine residue attacks the 2-position of the purine ring. A hydride ion is then transferred from the C2 position to NAD and the E-XMP* intermediate is formed. NADH dissociates from the enzyme and a mobile active-site flap element moves a conserved catalytic dyad of arginine and threonine into the newly unoccupied NAD binding site. The arginine residue is thought to act as the general base that activates a water molecule for the hydrolysis reaction.[4] Alternatively, molecular mechanics simulations suggest that in conditions where the arginine residue is protonated, the threonine residue is also capable of activating water by accepting a proton from water while transferring its own proton to a nearby residue.[25]

IMP dehydrogenase 1
Hgncid:6052
Symbol:IMPDH1
Altsymbols:RP10
Entrezgene:3614
Omim:146690
Refseq:NM_000883
Uniprot:P20839
Ecnumber:1.1.1.205
Chromosome:7
Arm:q
Band:31.3
Locussupplementarydata:-q32

In humans

IMP dehydrogenase 2
Caption:IMP dehydrogenase 2 homotetramer, Human
Width:270
Hgncid:6053
Symbol:IMPDH2
Altsymbols:IMPD2
Entrezgene:3615
Omim:146691
Refseq:NM_000884
Uniprot:P12268
Ecnumber:1.1.1.205
Chromosome:3
Arm:p
Band:21.2

Humans express two distinct isozymes of IMPDH encoded by two distinct genes, IMPDH1 and IMPDH2.

Both isozymes contain 514 residues, have an 84% similarity in peptide sequence, and have similar kinetic properties.[26] Both isozymes are constitutively expressed in most tissues, but IMPDH1 is predominately expressed in the spleen, retina, and peripheral blood leukocytes.[4] IMPDH1 is generally expressed constitutively at low levels, and IMPDH2 is generally upregulated in proliferating cells and neoplastic tissues.[27] [28] [29] Homozygous IMPDH1 knockout mice demonstrate a mild retinopathy in which a slow, progressive form of retinal degeneration gradually weakens visual transduction,[30] while homozygous IMPDH2 knockout mice display embryonic lethality.[31]

Clinical significance

Guanine nucleotide synthesis is essential for maintaining normal cell function and growth, and is also important for the maintenance of cell proliferation and immune responses. IMPDH expression is found to be upregulated in some tumor tissues and cell lines.[28] B and T lymphocytes display a dependence on IMPDH for normal activation and function,[32] [33] and demonstrate upregulated IMPDH expression.[29] Therefore, IMPDH has been addressed as a drug target for immunosuppressive and cancer chemotherapy.

Mycophenolate is an immunosuppressant that is used to prevent transplant rejection and acts through inhibition of IMPDH.

Mutations in the Bateman domain of IMPDH1 are associated with the RP10 form of autosomal dominant retinitis pigmentosa and dominant Leber's congenital amaurosis.[20]

Research

IMPDH inhibitors have been shown to prevent SARS-CoV-2 replication in cells[34] and are being tested in clinical trials for COVID-19.

See also

Further reading

Notes and References

  1. Hedstrom . Lizbeth . 2009-07-08 . IMP Dehydrogenase: Structure, Mechanism, and Inhibition . Chemical Reviews . en . 109 . 7 . 2903–2928 . 10.1021/cr900021w . 0009-2665 . 2737513 . 19480389.
  2. Ayoub . Nour . Gedeon . Antoine . Munier-Lehmann . Hélène . 2024-02-20 . A journey into the regulatory secrets of the de novo purine nucleotide biosynthesis . Frontiers in Pharmacology . English . 15 . 10.3389/fphar.2024.1329011 . free . 38444943 . 10912719 . 1663-9812.
  3. Sintchak MD, Nimmesgern E . The structure of inosine 5'-monophosphate dehydrogenase and the design of novel inhibitors . Immunopharmacology . 47 . 2–3 . 163–84 . May 2000 . 10878288 . 10.1016/S0162-3109(00)00193-4 .
  4. Hedstrom L . IMP dehydrogenase: structure, mechanism, and inhibition . Chemical Reviews . 109 . 7 . 2903–28 . July 2009 . 19480389 . 2737513 . 10.1021/cr900021w .
  5. Zhang R, Evans G, Rotella FJ, Westbrook EM, Beno D, Huberman E, Joachimiak A, Collart FR . April 1999 . Characteristics and crystal structure of bacterial inosine-5'-monophosphate dehydrogenase . Biochemistry . 38 . 15 . 4691–700 . 10.1.1.488.2542 . 10.1021/bi982858v . 10200156.
  6. Whitby FG, Luecke H, Kuhn P, Somoza JR, Huete-Perez JA, Phillips JD, Hill CP, Fletterick RJ, Wang CC . September 1997 . Crystal structure of Tritrichomonas foetus inosine-5'-monophosphate dehydrogenase and the enzyme-product complex . Biochemistry . 36 . 35 . 10666–74 . 10.1021/bi9708850 . 9271497.
  7. Prosise GL, Luecke H . February 2003 . Crystal structures of Tritrichomonasfoetus inosine monophosphate dehydrogenase in complex with substrate, cofactor and analogs: a structural basis for the random-in ordered-out kinetic mechanism . J. Mol. Biol. . 326 . 2 . 517–27 . 10.1016/S0022-2836(02)01383-9 . 12559919.
  8. Labesse . Gilles . Alexandre . Thomas . Vaupré . Laurène . Salard-Arnaud . Isabelle . Him . Joséphine Lai Kee . Raynal . Bertrand . Bron . Patrick . Munier-Lehmann . Hélène . 2013-06-04 . MgATP regulates allostery and fiber formation in IMPDHs . Structure (London, England: 1993) . 21 . 6 . 975–985 . 10.1016/j.str.2013.03.011 . 1878-4186 . 23643948.
  9. Magasanik B, Moyed HS, Gehring LB . Enzymes essential for the biosynthesis of nucleic acid guanine; inosine 5'-phosphate dehydrogenase of Aerobacter aerogenes . J. Biol. Chem. . 226 . 1 . 339–50 . May 1957 . 10.1016/S0021-9258(18)64835-5 . 13428767 . free .
  10. Xiang B, Taylor JC, Markham GD . Monovalent cation activation and kinetic mechanism of inosine 5'-monophosphate dehydrogenase . The Journal of Biological Chemistry . 271 . 3 . 1435–40 . January 1996 . 8576135 . 10.1074/jbc.271.3.1435 . free .
  11. Mortimer SE, Hedstrom L . Autosomal dominant retinitis pigmentosa mutations in inosine 5'-monophosphate dehydrogenase type I disrupt nucleic acid binding . The Biochemical Journal . 390 . Pt 1 . 41–7 . August 2005 . 15882147 . 1184561 . 10.1042/BJ20042051 .
  12. Nimmesgern E, Black J, Futer O, Fulghum JR, Chambers SP, Brummel CL, Raybuck SA, Sintchak MD . Biochemical analysis of the modular enzyme inosine 5'-monophosphate dehydrogenase . Protein Expression and Purification . 17 . 2 . 282–9 . November 1999 . 10545277 . 10.1006/prep.1999.1136 .
  13. Buey . Rubén M. . Ledesma-Amaro . Rodrigo . Velázquez-Campoy . Adrián . Balsera . Mónica . Chagoyen . Mónica . de Pereda . José M. . Revuelta . José L. . 2015-11-12 . Guanine nucleotide binding to the Bateman domain mediates the allosteric inhibition of eukaryotic IMP dehydrogenases . Nature Communications . en . 6 . 1 . 8923 . 10.1038/ncomms9923 . 26558346 . 4660370 . 2041-1723.
  14. Nimmesgern . E. . Black . J. . Futer . O. . Fulghum . J. R. . Chambers . S. P. . Brummel . C. L. . Raybuck . S. A. . Sintchak . M. D. . November 1999 . Biochemical analysis of the modular enzyme inosine 5'-monophosphate dehydrogenase . Protein Expression and Purification . 17 . 2 . 282–289 . 10.1006/prep.1999.1136 . 1046-5928 . 10545277.
  15. Gedeon . Antoine . Ayoub . Nour . Brûlé . Sébastien . Raynal . Bertrand . Karimova . Gouzel . Gelin . Muriel . Mechaly . Ariel . Haouz . Ahmed . Labesse . Gilles . Munier-Lehmann . Hélène . August 2023 . Insight into the role of the Bateman domain at the molecular and physiological levels through engineered IMP dehydrogenases . Protein Science . en . 32 . 8 . e4703 . 10.1002/pro.4703 . 0961-8368 . 10357500 . 37338125.
  16. Pimkin M, Pimkina J, Markham GD . A regulatory role of the Bateman domain of IMP dehydrogenase in adenylate nucleotide biosynthesis . The Journal of Biological Chemistry . 284 . 12 . 7960–9 . March 2009 . 19153081 . 2658089 . 10.1074/jbc.M808541200 . free .
  17. Pimkin . Maxim . Markham . George D. . April 2008 . The CBS subdomain of inosine 5'-monophosphate dehydrogenase regulates purine nucleotide turnover . Molecular Microbiology . 68 . 2 . 342–359 . 10.1111/j.1365-2958.2008.06153.x . 1365-2958 . 2279236 . 18312263.
  18. McLean JE, Hamaguchi N, Belenky P, Mortimer SE, Stanton M, Hedstrom L . Inosine 5'-monophosphate dehydrogenase binds nucleic acids in vitro and in vivo . The Biochemical Journal . 379 . Pt 2 . 243–51 . April 2004 . 14766016 . 1224093 . 10.1042/BJ20031585 .
  19. Cornuel . Jean-François . Moraillon . Anne . Guéron . Maurice . April 2002 . Participation of yeast inosine 5′-monophosphate dehydrogenase in an in vitro complex with a fragment of the C-rich telomeric strand . Biochimie . 84 . 4 . 279–289 . 10.1016/s0300-9084(02)01400-1 . 12106905 . 0300-9084.
  20. Bowne SJ, Sullivan LS, Mortimer SE, Hedstrom L, Zhu J, Spellicy CJ, Gire AI, Hughbanks-Wheaton D, Birch DG, Lewis RA, Heckenlively JR, Daiger SP . Spectrum and frequency of mutations in IMPDH1 associated with autosomal dominant retinitis pigmentosa and leber congenital amaurosis . Investigative Ophthalmology & Visual Science . 47 . 1 . 34–42 . January 2006 . 16384941 . 2581444 . 10.1167/iovs.05-0868 .
  21. Mortimer SE, Xu D, McGrew D, Hamaguchi N, Lim HC, Bowne SJ, Daiger SP, Hedstrom L . IMP dehydrogenase type 1 associates with polyribosomes translating rhodopsin mRNA . The Journal of Biological Chemistry . 283 . 52 . 36354–60 . December 2008 . 18974094 . 2605994 . 10.1074/jbc.M806143200 . free .
  22. Mölkänen . Tomi . Tyynelä . Jaana . Helin . Jari . Kalkkinen . Nisse . Kuusela . Pentti . 2002-04-24 . Enhanced activation of bound plasminogen on Staphylococcus aureus by staphylokinase . FEBS Letters . en . 517 . 1–3 . 72–78 . 10.1016/S0014-5793(02)02580-2 . 12062412 . 0014-5793.
  23. Kozhevnikova EN, van der Knaap JA, Pindyurin AV, Ozgur Z, van Ijcken WF, Moshkin YM, Verrijzer CP . Metabolic enzyme IMPDH is also a transcription factor regulated by cellular state . Molecular Cell . 47 . 1 . 133–9 . July 2012 . 22658723 . 10.1016/j.molcel.2012.04.030 . free .
  24. Collart FR, Huberman E . Cloning and sequence analysis of the human and Chinese hamster inosine-5'-monophosphate dehydrogenase cDNAs . J. Biol. Chem. . 263 . 30 . 15769–72 . October 1988 . 10.1016/S0021-9258(19)37654-9 . 2902093 . free .
  25. Min D, Josephine HR, Li H, Lakner C, MacPherson IS, Naylor GJ, Swofford D, Hedstrom L, Yang W . An enzymatic atavist revealed in dual pathways for water activation . PLOS Biology . 6 . 8 . e206 . August 2008 . 18752347 . 2525682 . 10.1371/journal.pbio.0060206 . free .
  26. Natsumeda Y, Ohno S, Kawasaki H, Konno Y, Weber G, Suzuki K . Two distinct cDNAs for human IMP dehydrogenase . The Journal of Biological Chemistry . 265 . 9 . 5292–5 . March 1990 . 10.1016/S0021-9258(19)34120-1 . 1969416 . free .
  27. Senda M, Natsumeda Y . Tissue-differential expression of two distinct genes for human IMP dehydrogenase (E.C.1.1.1.205) . Life Sciences . 54 . 24 . 1917–26 . 1994 . 7910933 . 10.1016/0024-3205(94)90150-3 .
  28. Collart FR, Chubb CB, Mirkin BL, Huberman E . Increased inosine-5'-phosphate dehydrogenase gene expression in solid tumor tissues and tumor cell lines . Cancer Research . 52 . 20 . 5826–8 . October 1992 . 1356621 . 10.2172/10148922 . free .
  29. Book: Zimmermann AG, Gu JJ, Laliberté J, Mitchell BS . Inosine-5'-monophosphate dehydrogenase: regulation of expression and role in cellular proliferation and T lymphocyte activation . 61 . 181–209 . 1998 . 9752721 . 10.1016/S0079-6603(08)60827-2 . 978-0-12-540061-9 . Progress in Nucleic Acid Research and Molecular Biology .
  30. Aherne A, Kennan A, Kenna PF, McNally N, Lloyd DG, Alberts IL, Kiang AS, Humphries MM, Ayuso C, Engel PC, Gu JJ, Mitchell BS, Farrar GJ, Humphries P . On the molecular pathology of neurodegeneration in IMPDH1-based retinitis pigmentosa . Human Molecular Genetics . 13 . 6 . 641–50 . March 2004 . 14981049 . 10.1093/hmg/ddh061 . free .
  31. Gu JJ, Tolin AK, Jain J, Huang H, Santiago L, Mitchell BS . Targeted disruption of the inosine 5'-monophosphate dehydrogenase type I gene in mice . Molecular and Cellular Biology . 23 . 18 . 6702–12 . September 2003 . 12944494 . 193693 . 10.1128/MCB.23.18.6702-6712.2003 .
  32. Jonsson CA, Carlsten H . Mycophenolic acid inhibits inosine 5'-monophosphate dehydrogenase and suppresses immunoglobulin and cytokine production of B cells . International Immunopharmacology . 3 . 1 . 31–7 . January 2003 . 12538032 . 10.1016/s1567-5769(02)00210-2 .
  33. Gu JJ, Stegmann S, Gathy K, Murray R, Laliberte J, Ayscue L, Mitchell BS . Inhibition of T lymphocyte activation in mice heterozygous for loss of the IMPDH II gene . The Journal of Clinical Investigation . 106 . 4 . 599–606 . August 2000 . 10953035 . 380246 . 10.1172/JCI8669 .
  34. Bojkova. Denisa. Klann. Kevin. Koch. Benjamin. Widera. Marek. Krause. David. Ciesek. Sandra. Cinatl. Jindrich. Münch. Christian. 2020-05-14. Proteomics of SARS-CoV-2-infected host cells reveals therapy targets. Nature. 583. 7816. en. 469–472. 10.1038/s41586-020-2332-7. 32408336. 2020Natur.583..469B. 1476-4687. free.

This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Inosine-5′-monophosphate dehydrogenase".

Except where otherwise indicated, Everything.Explained.Today is © Copyright 2009-2024, A B Cryer, All Rights Reserved. Cookie policy.