Formaldehyde dehydrogenase

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formaldehyde dehydrogenase
Identifiers
EC number 1.2.1.46
CAS number 9028-84-6
Databases
IntEnz IntEnz view
BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / EGO

In enzymology, a formaldehyde dehydrogenase (EC 1.2.1.46) is an enzyme that catalyzes the chemical reaction

formaldehyde + NAD+ + H2O \rightleftharpoons formate + NADH + H+

The 3 substrates of this enzyme are formaldehyde, NAD+, and H2O, whereas its 3 products are formate, NADH, and H+.

This enzyme belongs to the family of oxidoreductases, specifically those acting on the aldehyde or oxo group of donor with NAD+ or NADP+ as acceptor. The systematic name of this enzyme class is formaldehyde:NAD+ oxidoreductase. Other names in common use include NAD+-linked formaldehyde dehydrogenase, s-nitrosoglutathione reductase (GSNO reductase) and NAD+-dependent formaldehyde dehydrogenase. This enzyme participates in methane metabolism.

Ubiquitous function[edit]

S-nitrosoglutathione reductase (GSNOR) is a class III alcohol dehydrogenase (ADH) encoded by the ADH5 gene in humans. It is a primordial ADH that is ubiquitously expressed in plant and animals alike. GSNOR reduces S-nitrosoglutathione (GSNO) to the unstable intermediate, S-hydroxylaminoglutathione, which then rearranges to form glutathione sulfinamide, or in the presence of GSH, forms oxidized glutathione (GSSG) and hydroxyl amine.[1][2][3] Through this catabolic process, GSNOR regulates the cellular concentrations of GSNO and plays a central role in regulating the levels of endogenous S-nitrosothiols and controlling protein S-nitrosylation-based signaling. As an example of S-nitrosylation-based signaling, Barglow et al. showed that GSNO selectively S-nitrosylates reduced thioredoxin at cysteine 62.[4] Nitrosylated thioredoxin, via directed protein-protein interaction, trans-nitrosylates the active site cysteine of caspase-3 thus inactivating caspase-3 and preventing induction of apoptosis.[5]

As might be expected of an enzyme involved in regulating NO levels and signaling, pleiotropic effects are observed in GSNOR knockout models. Deleting the GSNOR gene from both yeast and mice increased the cellular levels of GSNO and nitrosylated proteins, and the yeast cells showed increased susceptibility to nitrosative stress.[6] Null mice show increased levels of S-nitrosated proteins, increased beta adrenergic receptor numbers in lung and heart,[7] diminished tachyphylaxis to β2-adrenergic receptor agonists, hyporesponsiveness to methacholine and allergen challenge and reduced infarct size after occlusion of the coronary artery.[8][9] In addition, null mice show increased tissue damage and mortality following challenge with bacteria or endotoxin and are hypotensive under anesthesia yet normotensive in the conscious state.[10] More related to its alcohol dehydrogenase activity, GSNOR null mice show a 30% reduction in the LD50 for formaldehyde and a decreased capacity to metabolize retinol, although it is clear from these studies that other pathways exist for the metabolism of these compounds.[11][12]

Role in disease[edit]

It has been shown that GSNOR may have an important role in respiratory diseases such as asthma. GSNOR expression has been inversely correlated with s-nitrosothiol (SNO) levels in the alveolar lining fluid in the lung and with responsiveness to methacholine challenge in patients with mild asthma compared to normal subjects.[13] Furthermore, there are lowered SNOs in tracheal irrigations in asthmatic children with respiratory failure in comparison to normal children undergoing elective surgery and NO species are elevated in asthma patients when exposed to antigen.[14]

Assessing the gene expression of the ADHs in nonalcoholic steatohepatitis (NASH) patients has shown elevated levels of all ADHs, but primarily ADH1 and ADH4 (up to 40-fold increased). ADH5 showed an ~4-fold increase in gene expression.[15]

Structural studies[edit]

As of late 2007, only one structure has been solved for this class of enzymes, with the PDB accession code 1KOL.

References[edit]

  1. ^ Jensen DE, Belka GK, Du Bois GC (April 1998). "S-Nitrosoglutathione is a substrate for rat alcohol dehydrogenase class III isoenzyme". Biochem. J. 331 (2): 659–68. PMC 1219401. PMID 9531510. 
  2. ^ Hedberg JJ, Griffiths WJ, Nilsson SJ, Höög JO (March 2003). "Reduction of S-nitrosoglutathione by human alcohol dehydrogenase 3 is an irreversible reaction as analysed by electrospray mass spectrometry". Eur. J. Biochem. 270 (6): 1249–56. doi:10.1046/j.1432-1033.2003.03486.x. PMID 12631283. 
  3. ^ Staab CA, Alander J, Morgenstern R, Grafström RC, Höög JO (March 2009). "The Janus face of alcohol dehydrogenase 3". Chem. Biol. Interact. 178 (1-3): 29–35. doi:10.1016/j.cbi.2008.10.050. PMID 19038239. 
  4. ^ Barglow KT, Knutson CG, Wishnok JS, Tannenbaum SR, Marletta MA (August 2011). "Site-specific and redox-controlled S-nitrosation of thioredoxin". Proc. Natl. Acad. Sci. U.S.A. 108 (35): E600–6. doi:10.1073/pnas.1110736108. PMC 3167493. PMID 21849622. 
  5. ^ Mitchell DA, Marletta MA (August 2005). "Thioredoxin catalyzes the S-nitrosation of the caspase-3 active site cysteine". Nat. Chem. Biol. 1 (3): 154–8. doi:10.1038/nchembio720. PMID 16408020. 
  6. ^ Liu L, Hausladen A, Zeng M, Que L, Heitman J, Stamler JS (March 2001). "A metabolic enzyme for S-nitrosothiol conserved from bacteria to humans". Nature 410 (6827): 490–4. doi:10.1038/35068596. PMID 11260719. 
  7. ^ Whalen EJ, Foster MW, Matsumoto A, Ozawa K, Violin JD, Que LG, Nelson CD, Benhar M, Keys JR, Rockman HA, Koch WJ, Daaka Y, Lefkowitz RJ, Stamler JS (May 2007). "Regulation of beta-adrenergic receptor signaling by S-nitrosylation of G-protein-coupled receptor kinase 2". Cell 129 (3): 511–22. doi:10.1016/j.cell.2007.02.046. PMID 17482545. 
  8. ^ Que LG, Liu L, Yan Y, Whitehead GS, Gavett SH, Schwartz DA, Stamler JS (June 2005). "Protection from experimental asthma by an endogenous bronchodilator". Science 308 (5728): 1618–21. doi:10.1126/science.1108228. PMC 2128762. PMID 15919956. 
  9. ^ Lima B, Lam GK, Xie L, Diesen DL, Villamizar N, Nienaber J, Messina E, Bowles D, Kontos CD, Hare JM, Stamler JS, Rockman HA (April 2009). "Endogenous S-nitrosothiols protect against myocardial injury". Proc. Natl. Acad. Sci. U.S.A. 106 (15): 6297–302. doi:10.1073/pnas.0901043106. PMC 2669330. PMID 19325130. 
  10. ^ Liu L, Yan Y, Zeng M, Zhang J, Hanes MA, Ahearn G, McMahon TJ, Dickfeld T, Marshall HE, Que LG, Stamler JS (February 2004). "Essential roles of S-nitrosothiols in vascular homeostasis and endotoxic shock". Cell 116 (4): 617–28. doi:10.1016/S0092-8674(04)00131-X. PMID 14980227. 
  11. ^ Molotkov A, Fan X, Deltour L, Foglio MH, Martras S, Farrés J, Parés X, Duester G (April 2002). "Stimulation of retinoic acid production and growth by ubiquitously expressed alcohol dehydrogenase Adh3". Proc. Natl. Acad. Sci. U.S.A. 99 (8): 5337–42. doi:10.1073/pnas.082093299. PMC 122770. PMID 11959987. 
  12. ^ Deltour L, Foglio MH, Duester G (June 1999). "Metabolic deficiencies in alcohol dehydrogenase Adh1, Adh3, and Adh4 null mutant mice. Overlapping roles of Adh1 and Adh4 in ethanol clearance and metabolism of retinol to retinoic acid". J. Biol. Chem. 274 (24): 16796–801. doi:10.1074/jbc.274.24.16796. PMID 10358022. 
  13. ^ Que LG, Yang Z, Stamler JS, Lugogo NL, Kraft M (August 2009). "S-nitrosoglutathione reductase: an important regulator in human asthma". Am. J. Respir. Crit. Care Med. 180 (3): 226–31. doi:10.1164/rccm.200901-0158OC. PMC 2724715. PMID 19395503. 
  14. ^ Dweik RA (June 2001). "The promise and reality of nitric oxide in the diagnosis and treatment of lung disease". Cleve Clin J Med 68 (6): 486, 488, 490, 493. PMID 11405609. 
  15. ^ Baker SS, Baker RD, Liu W, Nowak NJ, Zhu L (2010). "Role of alcohol metabolism in non-alcoholic steatohepatitis". PLoS ONE 5 (3): e9570. doi:10.1371/journal.pone.0009570. PMC 2833196. PMID 20221393. 

Further reading[edit]

  • Hohnloser W, Osswald B, Lingens F (1980). "Enzymological aspects of caffeine demethylation and formaldehyde oxidation by Pseudomonas putida C1". Hoppe. Seylers. Z. Physiol. Chem. 361 (12): 1763–6. doi:10.1515/bchm2.1980.361.2.1763. PMID 7461603.