Aldehyde dehydrogenases (ALDHs) constitute a superfamily of NAD(P)+-dependent enzymes, which detoxify aldehydes produced in various metabolic pathways to the corresponding carboxylic acids. Among the 19 human ALDHs, the cytosolic ALDH9A1 has so far never been fully enzymatically characterized and its structure is still unknown. Here, we report complete molecular and kinetic properties of human ALDH9A1 as well as three crystal forms at 2.3, 2.9, and 2.5 Å resolution. We show that ALDH9A1 exhibits wide substrate specificity to aminoaldehydes, aliphatic and aromatic aldehydes with a clear preference for γ-trimethylaminobutyraldehyde (TMABAL). The structure of ALDH9A1 reveals that the enzyme assembles as a tetramer. Each ALDH monomer displays a typical ALDHs fold composed of an oligomerization domain, a coenzyme domain, a catalytic domain, and an inter-domain linker highly conserved in amino-acid sequence and folding. Nonetheless, structural comparison reveals a position and a fold of the inter-domain linker of ALDH9A1 never observed in any other ALDH so far. This unique difference is not compatible with the presence of a bound substrate and a large conformational rearrangement of the linker up to 30 Å has to occur to allow the access of the substrate channel. Moreover, the αβE region consisting of an α-helix and a β-strand of the coenzyme domain at the dimer interface are disordered, likely due to the loss of interactions with the inter-domain linker, which leads to incomplete β-nicotinamide adenine dinucleotide (NAD+) binding pocket.

Department of Protein Biochemistry and Proteomics Centre of the Region Haná for Biotechnological and Agricultural Research Faculty of Science Palacký University Šlechtitelů 27 CZ 783 71 Olomouc Czech Republic

Institute for Integrative Biology of the Cell CNRS CEA Univ Paris Sud Université Paris Saclay Avenue de la Terrasse F 91198 Gif sur Yvette France

Zobrazit více v PubMed

Sophos N.A., Pappa A., Ziegler T.L. and Vasiliou V. (2001) Aldehyde dehydrogenase gene superfamily: the 2000 update. Chem. Biol. Interact. 130–132, 323–337 10.1016/S0009-2797(00)00275-1 PubMed DOI

Brocker C., Vasiliou M., Carpenter S., Carpenter C., Zhang Y., Wang X.. et al. (2013) Aldehyde dehydrogenase (ALDH) superfamily in plants: gene nomenclature and comparative genomics. Planta 237, 189–210 10.1007/s00425-012-1749-0 PubMed DOI PMC

Kurys G., Ambroziak W. and Pietruszko R. (1989) Human aldehyde dehydrogenase. Purification and characterization of a third isozyme with low K m for gamma-aminobutyraldehyde. J. Biol. Chem. 264, 4715–4721 PubMed

Suzuki O. and Matsumoto T. (1987) Purification and properties of diamine oxidase from human kidney. Biogenic. Amines. 4, 237–245

Lin S.W., Chen J.C., Hsu L.C., Hsieh C.L. and Yoshida A. (1996) Human gamma-aminobutyraldehyde dehydrogenase (ALDH9): cDNA sequence, genomic organization, polymorphism, chromosomal localization, and tissue expression. Genomics 34, 376–380 10.1006/geno.1996.0300 PubMed DOI

Kikonyogo A. and Pietruszko R. (1996) Aldehyde dehydrogenase from adult human brain that dehydrogenates gamma-aminobutyraldehyde: purification, characterization, cloning and distribution. Biochem. J. 316, 317–324 10.1042/bj3160317 PubMed DOI PMC

Ambroziak W. and Pietruszko R. (1991) Human aldehyde dehydrogenase. Activity with aldehyde metabolites of monoamines, diamines, and polyamines. J. Biol. Chem. 266, 13011–8 PubMed

Chern M.K. and Pietruszko R. (1995) Human aldehyde dehydrogenase E3 isozyme is a betaine aldehyde dehydrogenase. Biochem. Biophys. Res. Commun. 213, 561–568 10.1006/bbrc.1995.2168 PubMed DOI

McNeil S.D., Nuccio M.L. and Hanson A.D. (1999) Betaines and related osmoprotectants. Targets for metabolic engineering of stress resistance. Plant Physiol. 120, 945–950 PubMed PMC

Hulse J.D. and Henderson L.M. (1980) Carnitine biosynthesis. Purification of 4-N′-trimethylaminobutyraldehyde dehydrogenase from beef liver. J. Biol. Chem. 255, 1146–1151 PubMed

Vaz F.M., Fouchier S.W., Ofman R., Sommer M. and Wanders R.J. (2000) Molecular and biochemical characterization of rat γ-trimethylaminobutyraldehyde dehydrogenase and evidence for the involvement of human aldehyde dehydrogenase 9 in carnitine biosynthesis. J. Biol. Chem. 275, 7390–7394 10.1074/jbc.275.10.7390 PubMed DOI

Jakobs B.S. and Wanders R.J. (1995) Fatty acid beta-oxidation in peroxisomes and mitochondria: the first, unequivocal evidence for the involvement of carnitine in shuttling propionyl-CoA from peroxisomes to mitochondria. Biochem. Biophys. Res. Commun. 213, 1035–1041 10.1006/bbrc.1995.2232 PubMed DOI

Mandard S., Müller M. and Kersten S. (2004) Peroxisome proliferator-activated receptor alpha target genes. Cell Mol. Life Sci. 61, 393–416 10.1007/s00018-003-3216-3 PubMed DOI PMC

Wen G., Ringseis R., Rauer C. and Eder K. (2012) The mouse gene encoding the carnitine biosynthetic enzyme 4-N-trimethylaminobutyraldehyde dehydrogenase is regulated by peroxisome proliferator-activated receptor α. Biochim. Biophys. Acta 1819, 357–365 10.1016/j.bbagrm.2012.01.004 PubMed DOI

Matsunaga A., Harita Y., Shibagaki Y., Shimizu N., Shibuya K., Ono H.. et al. (2015) Identification of 4-trimethylaminobutyraldehyde Dehydrogenase (TMABA-DH) as a candidate serum autoantibody target for Kawasaki disease. PLoS ONE 10, e0128189 10.1371/journal.pone.0128189 PubMed DOI PMC

Sato W., Horie Y., Kataoka E., Ohshima S., Dohmen T., Iizuka M.. et al. (2006) Hepatic gene expression in hepatocyte-specific Pten deficient mice showing steatohepatitis without ethanol challenge. Hepatol. Res. 34, 256–265 10.1016/j.hepres.2006.01.003 PubMed DOI

Inada T., Koga M., Ishiguro H., Horiuchi Y., Syu A., Yoshio T.. et al. (2008) Pathway-based association analysis of genome-wide screening data suggest that genes associated with the gamma-aminobutyric acid receptor signaling pathway are involved in neuroleptic-induced, treatment-resistant tardive dyskinesia. Pharmacogenet. Genomics 18, 317–323 10.1097/FPC.0b013e3282f70492 PubMed DOI

Chen V.B., Arendall W.B. III, Headd J.J., Keedy D.A., Immormino R.M., Kapral G.J.. et al. (2010) MolProbity: all-atom structure validation for macromolecular crystallography. Acta Crystallogr. D Biol. Crystallogr. 66, 12–21 10.1107/S0907444909042073 PubMed DOI PMC

Johansson K., El-Ahmad M., Ramaswamy S., Hjelmqvist L., Jörnvall H. and Eklund H. (1998) Structure of betaine aldehyde dehydrogenase at 2.1 Å resolution. Protein Sci. 7, 2106–2117 10.1002/pro.5560071007 PubMed DOI PMC

Tylichová M., Kopečný D., Moréra S., Briozzo P., Lenobel R., Snégaroff J.. et al. (2010) Structural and functional characterization of plant aminoaldehyde dehydrogenase from Pisum sativum with a broad specificity for natural and synthetic aminoaldehydes. J. Mol. Biol. 396, 870–882 10.1016/j.jmb.2009.12.015 PubMed DOI

Kopečný D., Končitíková R., Tylichová M., Vigouroux A., Moskalíková H., Soural M.. et al. (2013) Plant ALDH10 family: identifying critical residues for substrate specificity and trapping a thiohemiacetal intermediate. J. Biol. Chem. 288, 9491–9507 10.1074/jbc.M112.443952 PubMed DOI PMC

Li W., Yuan X.M., Ivanova S., Tracey K.J., Eaton J.W. and Brunk U.T. (2003) 3-Aminopropanal, formed during cerebral ischaemia, is a potent lysosomotropic neurotoxin. Biochem. J. 371, 429–436 10.1042/bj20021520 PubMed DOI PMC

Murray-Stewart T., Wang Y., Devereux W. and Casero R.A. Jr (2002) Cloning and characterization of multiple human polyamine oxidase splice variants that code for isoenzymes with different biochemical characteristics. Biochem. J. 368, 673–677 10.1042/bj20021587 PubMed DOI PMC

Vujcic S., Diegelman P., Bacchi C.J., Kramer D.L. and Porter C.W. (2002) Identification and characterization of a novel flavin-containing spermine oxidase of mammalian cell origin. Biochem. J. 367, 665–675 10.1042/bj20020720 PubMed DOI PMC

Yoshida M., Tomitori H., Machi Y., Hagihara M., Higashi K., Goda H.. et al. (2009) Acrolein toxicity: Comparison with reactive oxygen species. Biochem. Biophys. Res. Commun. 378, 313–318 10.1016/j.bbrc.2008.11.054 PubMed DOI

Holt A. and Baker G.B. (1995) Metabolism of agmatine (clonidine-displacing substance) by diamine oxidase and the possible implications for studies of imidazoline receptors. Prog. Brain Res. 106, 187–197 10.1016/S0079-6123(08)61215-7 PubMed DOI

Iyer R.K., Kim H.K., Tsoa R.W., Grody W.W. and Cederbaum S.D. (2002) Cloning and characterization of human agmatinase. Mol. Genet. Metab. 75, 209–218 10.1006/mgme.2001.3277 PubMed DOI

Zhou Y., Holmseth S., Hua R., Lehre A.C., Olofsson A.M., Poblete-Naredo I.. et al. (2012) The betaine-GABA transporter (BGT1, slc6a12) is predominantly expressed in the liver and at lower levels in the kidneys and at the brain surface. Am. J. Physiol. Renal Physiol. 302, F316–F328 10.1152/ajprenal.00464.2011 PubMed DOI

Ueland P.M., Holm P.I. and Hustad S. (2005) Betaine: a key modulator of one-carbon metabolism and homocysteine status. Clin. Chem. Lab. Med. 43, 1069–1075 10.1515/CCLM.2005.187 PubMed DOI

Hjelmqvist L., Norin A., El-Ahmad M., Griffiths W. and Jörnvall H. (2003) Distinct but parallel evolutionary patterns between alcohol and aldehyde dehydrogenases: addition of fish/human betaine aldehyde dehydrogenase divergence. Cell Mol. Life Sci. 60, 2009–2016 10.1007/s00018-003-3287-1 PubMed DOI

Kim Y.G., Lee S., Kwon O.S., Park S.Y., Lee S.J., Park B.J.. et al. (2009) Redox-switch modulation of human SSADH by dynamic catalytic loop. EMBO J. 28, 959–968 10.1038/emboj.2009.40 PubMed DOI PMC

Šebela M., Brauner F., Radová A., Jacobsen S., Havliš J., Galuszka P.. et al. (2000) Characterisation of a homogeneous plant aminoaldehyde dehydrogenase. Biochim. Biophys. Acta 1480, 329–341 10.1016/S0167-4838(00)00086-8 PubMed DOI

Trossat C., Rathinasabapathi B. and Hanson A.D. (1997) Transgenically expressed betaine aldehyde dehydrogenase efficiently catalyzes oxidation of dimethylsulfoniopropionaldehyde and -aminoaldehydes. Plant Physiol. 113, 1457–1461 10.1104/pp.113.4.1457 PubMed DOI PMC

Kabsch W. (2010) XDS. Acta Crystallogr. D Biol. Crystallogr. 66, 125–132 10.1107/S0907444909047337 PubMed DOI PMC

Karplus P.A. and Diederichs K. (2012) Linking crystallographic model and data quality. Science 336, 1030–1033 10.1126/science.1218231 PubMed DOI PMC

Storoni L.C., McCoy A.J. and Read R.J. (2004) Likelihood-enhanced fast rotation functions. Acta Crystallogr. D Biol. Crystallogr. 60, 432–438 10.1107/S0907444903028956 PubMed DOI

Bricogne G., Blanc E., Brandl M., Flensburg C., Keller P., Paciorek W.. et al. (2017) BUSTER version 2.10.3, Global Phasing Ltd, Cambridge, United Kingdom

Emsley P. and Cowtan K. (2004) Coot: model-building tools for molecular graphics. Acta Crystallogr. D Biol. Crystallogr. 60, 2126–2132 10.1107/S0907444904019158 PubMed DOI

Polyamine-Derived Aminoaldehydes and Acrolein: Cytotoxicity, Reactivity and Analysis of the Induced Protein Modifications

Thinking outside the CaaX-box: an unusual reversible prenylation on ALDH9A1