Inosine-5′-monophosphate dehydrogenase

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Inosine 5'-monophosphate dehydrogenase
1PVN IMPDH Homotetramer.png
Structure of IMPDH [1]
Identifiers
EC no. 1.1.1.205
CAS no. 9028-93-7
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ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
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Gene Ontology AmiGO / QuickGO
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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. [2] [3] 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.

Contents

Structure and function

The canonical monomeric form of IMPDH has a molecular mass of approximately 55 kDa [4] and generally consists of 400-500 residues. [5] IMPDHs have been described as tetrameric, [6] [7] [8] although further data validated the existence of octameric forms. [9]

Visual representation of the active site with IMP (green) and NAD (purple) bound. Key residues (white) of the protein and the catalytic cysteine (cyan) are shown. Dashed lines represent polar contacts. 1NFB IMPDH Active Site.png
Visual representation of the active site with IMP (green) and NAD (purple) bound. Key residues (white) of the protein and the catalytic cysteine (cyan) are shown. Dashed lines represent polar contacts.

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. [5] [11] Monovalent cations have been shown to activate most IMPDH enzymes and may serve to stabilize the conformation of the active-site loop. [12]

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 . [13] [14] [15] [16] 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. [17] 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. [18] [19] IMPDH has also been shown to bind nucleic acids, [20] [21] and this function can be impaired by mutations that are located in the Bateman domain. [22] The Bateman domain has also been implicated in mediating IMPDH association with polyribosomes, [23] 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. [24] Drosophila IMPDH has been demonstrated to act as a sequence-specific transcriptional repressor that can reduce the expression of histone genes and E2F. [25] 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. [25]

Mechanism

General mechanism used by the enzyme IMPDH to convert IMP to XMP. Only the purine portion of each molecule is shown. IMPDH General Mechanism.png
General mechanism used by the enzyme IMPDH to convert IMP to XMP. Only the purine portion of each molecule is shown.

The overall reaction catalyzed by IMPDH is: [26]

inosine 5'-phosphate + NAD+ + H2O 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. [5] 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. [27]

IMP dehydrogenase 1
Identifiers
Symbol IMPDH1
Alt. symbolsRP10
NCBI gene 3614
HGNC 6052
OMIM 146690
RefSeq NM_000883
UniProt P20839
Other data
EC number 1.1.1.205
Locus Chr. 7 q31.3-q32
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Structures Swiss-model
Domains InterPro

In humans

IMP dehydrogenase 2
1nf7.jpg
IMP dehydrogenase 2 homotetramer, Human
Identifiers
Symbol IMPDH2
Alt. symbolsIMPD2
NCBI gene 3615
HGNC 6053
OMIM 146691
RefSeq NM_000884
UniProt P12268
Other data
EC number 1.1.1.205
Locus Chr. 3 p21.2
Search for
Structures Swiss-model
Domains InterPro

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. [28] Both isozymes are constitutively expressed in most tissues, but IMPDH1 is predominately expressed in the spleen, retina, and peripheral blood leukocytes. [5] IMPDH1 is generally expressed constitutively at low levels, and IMPDH2 is generally upregulated in proliferating cells and neoplastic tissues. [29] [30] [31] Homozygous IMPDH1 knockout mice demonstrate a mild retinopathy in which a slow, progressive form of retinal degeneration gradually weakens visual transduction, [32] while homozygous IMPDH2 knockout mice display embryonic lethality. [33]

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. [30] B and T lymphocytes display a dependence on IMPDH for normal activation and function, [34] [35] and demonstrate upregulated IMPDH expression. [31] 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. Mycophenolate mofetil has been shown to inhibit completely both vaccinia and monkeypox viruses. [36]

Mutations in the Bateman domain of IMPDH1 are associated with the RP10 form of autosomal dominant retinitis pigmentosa and dominant Leber's congenital amaurosis. [22]

Research

IMPDH inhibitors have been shown to prevent SARS-CoV-2 replication in cells [37] and are being tested in clinical trials for COVID-19. [38]

See also

Related Research Articles

<span class="mw-page-title-main">Nucleotide</span> Biological molecules constituting nucleic acids

Nucleotides are organic molecules composed of a nitrogenous base, a pentose sugar and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both of which are essential biomolecules within all life-forms on Earth. Nucleotides are obtained in the diet and are also synthesized from common nutrients by the liver.

<span class="mw-page-title-main">Inosine</span> Chemical compound

Inosine is a nucleoside that is formed when hypoxanthine is attached to a ribose ring (also known as a ribofuranose) via a β-N9-glycosidic bond. It was discovered in 1965 in analysis of RNA transferase. Inosine is commonly found in tRNAs and is essential for proper translation of the genetic code in wobble base pairs.

<span class="mw-page-title-main">Ribonucleotide</span> Nucleotide containing ribose as its pentose component

In biochemistry, a ribonucleotide is a nucleotide containing ribose as its pentose component. It is considered a molecular precursor of nucleic acids. Nucleotides are the basic building blocks of DNA and RNA. Ribonucleotides themselves are basic monomeric building blocks for RNA. Deoxyribonucleotides, formed by reducing ribonucleotides with the enzyme ribonucleotide reductase (RNR), are essential building blocks for DNA. There are several differences between DNA deoxyribonucleotides and RNA ribonucleotides. Successive nucleotides are linked together via phosphodiester bonds.

<span class="mw-page-title-main">Mycophenolic acid</span> Immunosuppressant medication

Mycophenolic acid is an immunosuppressant medication used to prevent rejection following organ transplantation and to treat autoimmune conditions such as Crohn's disease and lupus. Specifically it is used following kidney, heart, and liver transplantation. It can be given by mouth or by injection into a vein. It comes as mycophenolate sodium and mycophenolate mofetil.

A nucleoside triphosphate is a nucleoside containing a nitrogenous base bound to a 5-carbon sugar, with three phosphate groups bound to the sugar. They are the molecular precursors of both DNA and RNA, which are chains of nucleotides made through the processes of DNA replication and transcription. Nucleoside triphosphates also serve as a source of energy for cellular reactions and are involved in signalling pathways.

<span class="mw-page-title-main">Hypoxanthine-guanine phosphoribosyltransferase</span> Enzyme that converts hypoxanthine to inosine monophosphate

Hypoxanthine-guanine phosphoribosyltransferase (HGPRT) is an enzyme encoded in humans by the HPRT1 gene.

<span class="mw-page-title-main">Inosinic acid</span> Chemical compound

Inosinic acid or inosine monophosphate (IMP) is a nucleotide. Widely used as a flavor enhancer, it is typically obtained from chicken byproducts or other meat industry waste. Inosinic acid is important in metabolism. It is the ribonucleotide of hypoxanthine and the first nucleotide formed during the synthesis of purine nucleotides. It can also be formed by the deamination of adenosine monophosphate by AMP deaminase. It can be hydrolysed to inosine.

<span class="mw-page-title-main">Purine nucleoside phosphorylase</span> Enzyme

Purine nucleoside phosphorylase, PNP, PNPase or inosine phosphorylase is an enzyme that in humans is encoded by the NP gene. It catalyzes the chemical reaction

<span class="mw-page-title-main">Nucleic acid metabolism</span> Process

Nucleic acid metabolism is a collective term that refers to the variety of chemical reactions by which nucleic acids are either synthesized or degraded. Nucleic acids are polymers made up of a variety of monomers called nucleotides. Nucleotide synthesis is an anabolic mechanism generally involving the chemical reaction of phosphate, pentose sugar, and a nitrogenous base. Degradation of nucleic acids is a catabolic reaction and the resulting parts of the nucleotides or nucleobases can be salvaged to recreate new nucleotides. Both synthesis and degradation reactions require multiple enzymes to facilitate the event. Defects or deficiencies in these enzymes can lead to a variety of diseases.

Purine metabolism refers to the metabolic pathways to synthesize and break down purines that are present in many organisms.

<span class="mw-page-title-main">Xanthosine monophosphate</span> Chemical compound

Xanthosine monophosphate (xanthylate) is an intermediate in purine metabolism. It is a ribonucleoside monophosphate. It is formed from IMP via the action of IMP dehydrogenase, and it forms GMP via the action of GMP synthase. Also, XMP can be released from XTP by enzyme deoxyribonucleoside triphosphate pyrophosphohydrolase containing (d)XTPase activity.

<span class="mw-page-title-main">GMP synthase</span> Protein domain

Guanosine monophosphate synthetase, also known as GMPS is an enzyme that converts xanthosine monophosphate to guanosine monophosphate.

<span class="mw-page-title-main">GMP reductase</span> Class of enzymes

GMP reductase EC 1.7.1.7 is an enzyme that catalyzes the irreversible and NADPH-dependent reductive deamination of GMP into IMP.

In enzymology, an adenosine-phosphate deaminase (EC 3.5.4.17) is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">IMPDH1</span> Protein-coding gene in the species Homo sapiens

Inosine-5'-monophosphate dehydrogenase 1, also known as IMP dehydrogenase 1, is an enzyme that in humans is encoded by the IMPDH1 gene.

<span class="mw-page-title-main">Phosphoribosylglycinamide formyltransferase</span>

Phosphoribosylglycinamide formyltransferase (EC 2.1.2.2), also known as glycinamide ribonucleotide transformylase (GAR Tfase), is an enzyme with systematic name 10-formyltetrahydrofolate:5'-phosphoribosylglycinamide N-formyltransferase. This enzyme catalyses the following chemical reaction

<span class="mw-page-title-main">CBS domain</span> Protein domain

In molecular biology, the CBS domain is a protein domain found in a range of proteins in all species from bacteria to humans. It was first identified as a conserved sequence region in 1997 and named after cystathionine beta synthase, one of the proteins it is found in. CBS domains are also found in a wide variety of other proteins such as inosine monophosphate dehydrogenase, voltage gated chloride channels and AMP-activated protein kinase (AMPK). CBS domains regulate the activity of associated enzymatic and transporter domains in response to binding molecules with adenosyl groups such as AMP and ATP, or s-adenosylmethionine.

<span class="mw-page-title-main">IMPDH2</span> Protein-coding gene in the species Homo sapiens

Inosine-5'-monophosphate dehydrogenase 2, also known as IMP dehydrogenase 2, is an enzyme that in humans is encoded by the IMPDH2 gene.

<span class="mw-page-title-main">Purine nucleotide cycle</span> Protein metabolic pathway

The Purine Nucleotide Cycle is a metabolic pathway in protein metabolism requiring the amino acids aspartate and glutamate. The cycle is used to regulate the levels of adenine nucleotides, in which ammonia and fumarate are generated. AMP converts into IMP and the byproduct ammonia. IMP converts to S-AMP (adenylosuccinate), which then converts to AMP and the byproduct fumarate. The fumarate goes on to produce ATP (energy) via oxidative phosphorylation as it enters the Krebs cycle and then the electron transport chain. Lowenstein first described this pathway and outlined its importance in processes including amino acid catabolism and regulation of flux through glycolysis and the Krebs cycle.

The gua operon is responsible for regulating the synthesis of guanosine mono phosphate (GMP), a purine nucleotide, from inosine monophosphate. It consists of two structural genes guaB (encodes for IMP dehydrogenase or and guaA apart from the promoter and operator region.

References

  1. ↑ Gan L, Seyedsayamdost MR, Shuto S, Matsuda A, Petsko GA, Hedstrom L (February 2003). "The immunosuppressive agent mizoribine monophosphate forms a transition state analogue complex with inosine monophosphate dehydrogenase". Biochemistry. 42 (4): 857–63. doi:10.1021/bi0271401. PMID   12549902.
  2. ↑ Hedstrom, Lizbeth (2009-07-08). "IMP Dehydrogenase: Structure, Mechanism, and Inhibition". Chemical Reviews. 109 (7): 2903–2928. doi:10.1021/cr900021w. ISSN   0009-2665. PMC   2737513 . PMID   19480389.
  3. ↑ 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. 15. doi: 10.3389/fphar.2024.1329011 . ISSN   1663-9812. PMC   10912719 . PMID   38444943.
  4. ↑ Sintchak MD, Nimmesgern E (May 2000). "The structure of inosine 5'-monophosphate dehydrogenase and the design of novel inhibitors". Immunopharmacology. 47 (2–3): 163–84. doi:10.1016/S0162-3109(00)00193-4. PMID   10878288.
  5. 1 2 3 4 Hedstrom L (July 2009). "IMP dehydrogenase: structure, mechanism, and inhibition". Chemical Reviews. 109 (7): 2903–28. doi:10.1021/cr900021w. PMC   2737513 . PMID   19480389.
  6. ↑ 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. CiteSeerX   10.1.1.488.2542 . doi:10.1021/bi982858v. PMID   10200156.
  7. ↑ 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. doi:10.1021/bi9708850. PMID   9271497.
  8. ↑ 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". Journal of Molecular Biology. 326 (2): 517–27. doi:10.1016/S0022-2836(02)01383-9. PMID   12559919.
  9. ↑ 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. 21 (6): 975–985. doi:10.1016/j.str.2013.03.011. ISSN   1878-4186. PMID   23643948.
  10. ↑ PDB ID: 1NFB, Risal, D., Strickler M,D., Goldstein, B.M.,The Conformation of NAD Bound to Human Inosine Monophosphate Dehydrogenase Type II.
  11. ↑ Magasanik B, Moyed HS, Gehring LB (May 1957). "Enzymes essential for the biosynthesis of nucleic acid guanine; inosine 5'-phosphate dehydrogenase of Aerobacter aerogenes". J. Biol. Chem. 226 (1): 339–50. doi: 10.1016/S0021-9258(18)64835-5 . PMID   13428767.
  12. ↑ Xiang B, Taylor JC, Markham GD (January 1996). "Monovalent cation activation and kinetic mechanism of inosine 5'-monophosphate dehydrogenase". The Journal of Biological Chemistry. 271 (3): 1435–40. doi: 10.1074/jbc.271.3.1435 . PMID   8576135.
  13. ↑ Mortimer SE, Hedstrom L (August 2005). "Autosomal dominant retinitis pigmentosa mutations in inosine 5'-monophosphate dehydrogenase type I disrupt nucleic acid binding". The Biochemical Journal. 390 (Pt 1): 41–7. doi:10.1042/BJ20042051. PMC   1184561 . PMID   15882147.
  14. ↑ Nimmesgern E, Black J, Futer O, Fulghum JR, Chambers SP, Brummel CL, Raybuck SA, Sintchak MD (November 1999). "Biochemical analysis of the modular enzyme inosine 5'-monophosphate dehydrogenase". Protein Expression and Purification. 17 (2): 282–9. doi:10.1006/prep.1999.1136. PMID   10545277.
  15. ↑ 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. 6 (1): 8923. Bibcode:2015NatCo...6.8923B. doi:10.1038/ncomms9923. ISSN   2041-1723. PMC   4660370 . PMID   26558346.
  16. ↑ 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. doi:10.1006/prep.1999.1136. ISSN   1046-5928. PMID   10545277.
  17. ↑ 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. 32 (8): e4703. doi:10.1002/pro.4703. ISSN   0961-8368. PMC   10357500 . PMID   37338125.
  18. ↑ Pimkin M, Pimkina J, Markham GD (March 2009). "A regulatory role of the Bateman domain of IMP dehydrogenase in adenylate nucleotide biosynthesis". The Journal of Biological Chemistry. 284 (12): 7960–9. doi: 10.1074/jbc.M808541200 . PMC   2658089 . PMID   19153081.
  19. ↑ 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. doi:10.1111/j.1365-2958.2008.06153.x. ISSN   1365-2958. PMC   2279236 . PMID   18312263.
  20. ↑ McLean JE, Hamaguchi N, Belenky P, Mortimer SE, Stanton M, Hedstrom L (April 2004). "Inosine 5'-monophosphate dehydrogenase binds nucleic acids in vitro and in vivo". The Biochemical Journal. 379 (Pt 2): 243–51. doi:10.1042/BJ20031585. PMC   1224093 . PMID   14766016.
  21. ↑ 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. doi:10.1016/s0300-9084(02)01400-1. ISSN   0300-9084. PMID   12106905.
  22. 1 2 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 (January 2006). "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. doi:10.1167/iovs.05-0868. PMC   2581444 . PMID   16384941.
  23. ↑ Mortimer SE, Xu D, McGrew D, Hamaguchi N, Lim HC, Bowne SJ, Daiger SP, Hedstrom L (December 2008). "IMP dehydrogenase type 1 associates with polyribosomes translating rhodopsin mRNA". The Journal of Biological Chemistry. 283 (52): 36354–60. doi: 10.1074/jbc.M806143200 . PMC   2605994 . PMID   18974094.
  24. ↑ 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. 517 (1–3): 72–78. Bibcode:2002FEBSL.517...72M. doi:10.1016/S0014-5793(02)02580-2. ISSN   0014-5793. PMID   12062412.
  25. 1 2 Kozhevnikova EN, van der Knaap JA, Pindyurin AV, Ozgur Z, van Ijcken WF, Moshkin YM, Verrijzer CP (July 2012). "Metabolic enzyme IMPDH is also a transcription factor regulated by cellular state". Molecular Cell. 47 (1): 133–9. doi: 10.1016/j.molcel.2012.04.030 . PMID   22658723.
  26. ↑ Collart FR, Huberman E (October 1988). "Cloning and sequence analysis of the human and Chinese hamster inosine-5'-monophosphate dehydrogenase cDNAs". J. Biol. Chem. 263 (30): 15769–72. doi: 10.1016/S0021-9258(19)37654-9 . PMID   2902093.
  27. ↑ Min D, Josephine HR, Li H, Lakner C, MacPherson IS, Naylor GJ, Swofford D, Hedstrom L, Yang W (August 2008). "An enzymatic atavist revealed in dual pathways for water activation". PLOS Biology. 6 (8): e206. doi: 10.1371/journal.pbio.0060206 . PMC   2525682 . PMID   18752347.
  28. ↑ Natsumeda Y, Ohno S, Kawasaki H, Konno Y, Weber G, Suzuki K (March 1990). "Two distinct cDNAs for human IMP dehydrogenase". The Journal of Biological Chemistry. 265 (9): 5292–5. doi: 10.1016/S0021-9258(19)34120-1 . PMID   1969416.
  29. ↑ Senda M, Natsumeda Y (1994). "Tissue-differential expression of two distinct genes for human IMP dehydrogenase (E.C.1.1.1.205)". Life Sciences. 54 (24): 1917–26. doi:10.1016/0024-3205(94)90150-3. PMID   7910933.
  30. 1 2 Collart FR, Chubb CB, Mirkin BL, Huberman E (October 1992). "Increased inosine-5'-phosphate dehydrogenase gene expression in solid tumor tissues and tumor cell lines". Cancer Research. 52 (20): 5826–8. doi: 10.2172/10148922 . PMID   1356621.
  31. 1 2 Zimmermann AG, Gu JJ, Laliberté J, Mitchell BS (1998). Inosine-5'-monophosphate dehydrogenase: regulation of expression and role in cellular proliferation and T lymphocyte activation. Progress in Nucleic Acid Research and Molecular Biology. Vol. 61. pp. 181–209. doi:10.1016/S0079-6603(08)60827-2. ISBN   978-0-12-540061-9. PMID   9752721.
  32. ↑ 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 (March 2004). "On the molecular pathology of neurodegeneration in IMPDH1-based retinitis pigmentosa". Human Molecular Genetics. 13 (6): 641–50. doi: 10.1093/hmg/ddh061 . PMID   14981049.
  33. ↑ Gu JJ, Tolin AK, Jain J, Huang H, Santiago L, Mitchell BS (September 2003). "Targeted disruption of the inosine 5'-monophosphate dehydrogenase type I gene in mice". Molecular and Cellular Biology. 23 (18): 6702–12. doi:10.1128/MCB.23.18.6702-6712.2003. PMC   193693 . PMID   12944494.
  34. ↑ Jonsson CA, Carlsten H (January 2003). "Mycophenolic acid inhibits inosine 5'-monophosphate dehydrogenase and suppresses immunoglobulin and cytokine production of B cells". International Immunopharmacology. 3 (1): 31–7. doi:10.1016/s1567-5769(02)00210-2. PMID   12538032.
  35. ↑ Gu JJ, Stegmann S, Gathy K, Murray R, Laliberte J, Ayscue L, Mitchell BS (August 2000). "Inhibition of T lymphocyte activation in mice heterozygous for loss of the IMPDH II gene". The Journal of Clinical Investigation. 106 (4): 599–606. doi:10.1172/JCI8669. PMC   380246 . PMID   10953035.
  36. ↑ Witwit, Haydar; Cubitt, Beatrice; Khafaji, Roaa; Castro, Esteban M.; Goicoechea, Miguel; Lorenzo, Maria M.; Blasco, Rafael; Martinez-Sobrido, Luis; de la Torre, Juan C. (January 2025). "Repurposing Drugs for Synergistic Combination Therapies to Counteract Monkeypox Virus Tecovirimat Resistance". Viruses. 17 (1): 92. doi: 10.3390/v17010092 . ISSN   1999-4915.
  37. ↑ 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): 469–472. Bibcode:2020Natur.583..469B. doi: 10.1038/s41586-020-2332-7 . ISSN   1476-4687. PMC   7616921 . PMID   32408336.
  38. ↑ Clinical trial number NCT04356677 for "Study to Evaluate the Safety and Efficacy of VIRAZOLE® in Hospitalized Adult Participants With Respiratory Distress Due to COVID-19" at ClinicalTrials.gov

Further reading

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