DB code: D00021

RLCP classification	4.501.3813400.59 : Addition
	9.1050.584160.160 : Hydride transfer
	1.14.200.137 : Hydrolysis
CATH domain	3.40.605.10 : Aldehyde Dehydrogenase; Chain A, domain 1	Catalytic domain
CATH domain	3.40.309.10 : Aldehyde Dehydrogenase; Chain A, domain 2	Catalytic domain
E.C.	1.2.1.8 1.2.1.3
CSA	1a4s
M-CSA	1a4s
MACiE	M0100

CATH domain	Related DB codes (homologues)
3.40.309.10 : Aldehyde Dehydrogenase; Chain A, domain 2	D00020 D00022 D00475 D00614
3.40.605.10 : Aldehyde Dehydrogenase; Chain A, domain 1	D00020 D00022 D00475 D00614

Uniprot Enzyme Name
UniprotKB	Protein name	Synonyms	Pfam
P56533	Betaine aldehyde dehydrogenase	BADH EC 1.2.1.8 Aldehyde dehydrogenase family 9 member A1 EC 1.2.1.3	PF00171 (Aldedh) [Graphical View]

KEGG enzyme name
betaine-aldehyde dehydrogenase (EC 1.2.1.8 ) betaine aldehyde oxidase (EC 1.2.1.8 ) BADH (EC 1.2.1.8 ) betaine aldehyde dehydrogenase (EC 1.2.1.8 ) BetB (EC 1.2.1.8 ) aldehyde dehydrogenase (NAD+) (EC 1.2.1.3 ) CoA-independent aldehyde dehydrogenase (EC 1.2.1.3 ) m-methylbenzaldehyde dehydrogenase (EC 1.2.1.3 ) NAD-aldehyde dehydrogenase (EC 1.2.1.3 ) NAD-dependent 4-hydroxynonenal dehydrogenase (EC 1.2.1.3 ) NAD-dependent aldehyde dehydrogenase (EC 1.2.1.3 ) NAD-linked aldehyde dehydrogenase (EC 1.2.1.3 ) propionaldehyde dehydrogenase (EC 1.2.1.3 ) aldehyde dehydrogenase (NAD) (EC 1.2.1.3 )

KEGG enzyme name

betaine-aldehyde dehydrogenase
(EC 1.2.1.8 )
betaine aldehyde oxidase
(EC 1.2.1.8 )
BADH
(EC 1.2.1.8 )
betaine aldehyde dehydrogenase
(EC 1.2.1.8 )
BetB
(EC 1.2.1.8 )
aldehyde dehydrogenase (NAD+)
(EC 1.2.1.3 )
CoA-independent aldehyde dehydrogenase
(EC 1.2.1.3 )
m-methylbenzaldehyde dehydrogenase
(EC 1.2.1.3 )
NAD-aldehyde dehydrogenase
(EC 1.2.1.3 )
NAD-dependent 4-hydroxynonenal dehydrogenase
(EC 1.2.1.3 )
NAD-dependent aldehyde dehydrogenase
(EC 1.2.1.3 )
NAD-linked aldehyde dehydrogenase
(EC 1.2.1.3 )
propionaldehyde dehydrogenase
(EC 1.2.1.3 )
aldehyde dehydrogenase (NAD)
(EC 1.2.1.3 )

UniprotKB: Accession Number	Entry name	Activity	Subunit	Subcellular location	Cofactor
P56533	BADH_GADCA	Betaine aldehyde + NAD(+) + H(2)O = betaine + NADH. An aldehyde + NAD(+) + H(2)O = an acid + NADH.	Homotetramer.	Cytoplasm (By similarity).

KEGG Pathways
Map code	Pathways	E.C.
MAP00010	Glycolysis / Gluconeogenesis	1.2.1.3
MAP00053	Ascorbate and aldarate metabolism	1.2.1.3
MAP00071	Fatty acid metabolism	1.2.1.3
MAP00120	Bile acid biosynthesis	1.2.1.3
MAP00220	Urea cycle and metabolism of amino groups	1.2.1.3
MAP00260	Glycine, serine and threonine metabolism	1.2.1.8
MAP00280	Valine, leucine and isoleucine degradation	1.2.1.3
MAP00310	Lysine degradation	1.2.1.3
MAP00340	Histidine metabolism	1.2.1.3
MAP00380	Tryptophan metabolism	1.2.1.3
MAP00410	beta-Alanine metabolism	1.2.1.3
MAP00561	Glycerolipid metabolism	1.2.1.3
MAP00620	Pyruvate metabolism	1.2.1.3
MAP00631	1,2-Dichloroethane degradation	1.2.1.3
MAP00640	Propanoate metabolism	1.2.1.3
MAP00641	3-Chloroacrylic acid degradation	1.2.1.3
MAP00650	Butanoate metabolism	1.2.1.3
MAP00903	Limonene and pinene degradation	1.2.1.3

Compound table
	Substrates				Products				Intermediates
KEGG-id	C00576	C00071	C00003	C00001	C00719	C00174	C00004	C00080	I00156	I00154	I00155
E.C.	1.2.1.8	1.2.1.3	1.2.1.8 1.2.1.3	1.2.1.8 1.2.1.3	1.2.1.8	1.2.1.3	1.2.1.8 1.2.1.3	1.2.1.8 1.2.1.3	1.2.1.8 1.2.1.3	1.2.1.8 1.2.1.3	1.2.1.8 1.2.1.3
Compound	Betaine aldehyde	Aldehyde	NAD+	H2O	Betaine	Acid	NADH	H+	Peptidyl-Cys-alcohol-intermediate	Acyl-enzyme(Peptidyl-Cys-acyl group)	Peptidyl-Cys-tetrahedral-intermediate
Type	amine group,carbohydrate	carbohydrate	amide group,amine group,nucleotide	H2O	amine group,carboxyl group	carboxyl group	amide group,amine group,nucleotide	others
ChEBI	15710 15710		15846 15846	15377 15377	17750 17750		16908 16908	15378 15378
PubChem	249 249		5893 5893	22247451 962 22247451 962	247 247		439153 439153	1038 1038

1a4sA01	Unbound	Unbound	Unbound		Unbound	Unbound	Unbound		Unbound	Unbound	Unbound
1a4sB01	Unbound	Unbound	Unbound		Unbound	Unbound	Unbound		Unbound	Unbound	Unbound
1a4sC01	Unbound	Unbound	Unbound		Unbound	Unbound	Unbound		Unbound	Unbound	Unbound
1a4sD01	Unbound	Unbound	Unbound		Unbound	Unbound	Unbound		Unbound	Unbound	Unbound
1bpwA01	Unbound	Unbound	Bound:NAD		Unbound	Unbound	Unbound		Unbound	Unbound	Unbound
1bpwB01	Unbound	Unbound	Bound:NAD		Unbound	Unbound	Unbound		Unbound	Unbound	Unbound
1bpwC01	Unbound	Unbound	Bound:NAD		Unbound	Unbound	Unbound		Unbound	Unbound	Unbound
1bpwD01	Unbound	Unbound	Bound:NAD		Unbound	Unbound	Unbound		Unbound	Unbound	Unbound
1a4sA02	Unbound	Unbound	Unbound		Unbound	Unbound	Unbound		Unbound	Unbound	Unbound
1a4sB02	Unbound	Unbound	Unbound		Unbound	Unbound	Unbound		Unbound	Unbound	Unbound
1a4sC02	Unbound	Unbound	Unbound		Unbound	Unbound	Unbound		Unbound	Unbound	Unbound
1a4sD02	Unbound	Unbound	Unbound		Unbound	Unbound	Unbound		Unbound	Unbound	Unbound
1bpwA02	Unbound	Unbound	Unbound		Unbound	Unbound	Unbound		Unbound	Unbound	Unbound
1bpwB02	Unbound	Unbound	Unbound		Unbound	Unbound	Unbound		Unbound	Unbound	Unbound
1bpwC02	Unbound	Unbound	Unbound		Unbound	Unbound	Unbound		Unbound	Unbound	Unbound
1bpwD02	Unbound	Unbound	Unbound		Unbound	Unbound	Unbound		Unbound	Unbound	Unbound

Reference for Active-site residues
resource	references	E.C.
literature [5]

Active-site residues
PDB	Catalytic residues	Cofactor-binding residues	Modified residues	Main-chain involved in catalysis	Comment

1a4sA01	ASN 166;GLU 263
1a4sB01	ASN 166;GLU 263
1a4sC01	ASN 166;GLU 263
1a4sD01	ASN 166;GLU 263
1bpwA01	ASN 166;GLU 263
1bpwB01	ASN 166;GLU 263
1bpwC01	ASN 166;GLU 263
1bpwD01	ASN 166;GLU 263
1a4sA02	CYS 297			CYS 297
1a4sB02	CYS 297			CYS 297
1a4sC02	CYS 297			CYS 297
1a4sD02	CYS 297			CYS 297
1bpwA02	CYS 297			CYS 297
1bpwB02	CYS 297			CYS 297
1bpwC02	CYS 297			CYS 297
1bpwD02	CYS 297			CYS 297

References for Catalytic Mechanism
References	Sections	No. of steps in catalysis
[2]	p.239-242
[3]	p.706-709
[5]	p.2114-2115
[6]	p.1546-1549

References
[1]
Resource
Comments
Medline ID
PubMed ID	8269919
Journal	Eur J Biochem
Year	1993
Volume	218
Pages	311-20
Authors	Kurys G, Shah PC, Kikonygo A, Reed D, Ambroziak W, Pietruszko R
Title	Human aldehyde dehydrogenase. cDNA cloning and primary structure of the enzyme that catalyzes dehydrogenation of 4-aminobutyraldehyde.
Related PDB
Related UniProtKB
[2]
Resource
Comments
Medline ID
PubMed ID	7819202
Journal	Biochemistry
Year	1995
Volume	34
Pages	237-43
Authors	Wang X, Weiner H
Title	Involvement of glutamate 268 in the active site of human liver mitochondrial (class 2) aldehyde dehydrogenase as probed by site-directed mutagenesis.
Related PDB
Related UniProtKB
[3]
Resource
Comments
Medline ID
PubMed ID	9195888
Journal	Structure
Year	1997
Volume	5
Pages	701-11
Authors	Steinmetz CG, Xie P, Weiner H, Hurley TD
Title	Structure of mitochondrial aldehyde dehydrogenase: the genetic component of ethanol aversion.
Related PDB
Related UniProtKB
[4]
Resource
Comments
Medline ID
PubMed ID	9228057
Journal	J Biol Chem
Year	1997
Volume	272
Pages	18823-6
Authors	Ni L, Sheikh S, Weiner H
Title	Involvement of glutamate 399 and lysine 192 in the mechanism of human liver mitochondrial aldehyde dehydrogenase.
Related PDB
Related UniProtKB
[5]
Resource
Comments	X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS)
Medline ID	99006561
PubMed ID	9792097
Journal	Protein Sci
Year	1998
Volume	7
Pages	2106-17
Authors	Johansson K, El-Ahmad M, Ramaswamy S, Hjelmqvist L, Jornvall H, Eklund H
Title	Structure of betaine aldehyde dehydrogenase at 2.1 A resolution.
Related PDB	1a4s 1bpw
Related UniProtKB	P56533
[6]
Resource
Comments
Medline ID
PubMed ID	9862807
Journal	Structure
Year	1998
Volume	6
Pages	1541-51
Authors	Moore SA, Baker HM, Blythe TJ, Kitson KE, Kitson TM, Baker EN
Title	Sheep liver cytosolic aldehyde dehydrogenase: the structure reveals the basis for the retinal specificity of class 1 aldehyde dehydrogenases.
Related PDB	1bxs
Related UniProtKB
[7]
Resource
Comments
Medline ID
PubMed ID	10352667
Journal	Adv Exp Med Biol
Year	1999
Volume	463
Pages	39-44
Authors	Hjelmqvist L, el-Ahmad M, Johansson K, Norin A, Ramaswamy S, Jornvall H
Title	Structure and function of betaine aldehyde dehydrogenase. An enzyme within the multienzyme aldehyde dehydrogenase system.
Related PDB
Related UniProtKB
[8]
Resource
Comments
Medline ID
PubMed ID	10631996
Journal	Protein Sci
Year	1999
Volume	8
Pages	2784-90
Authors	Ni L, Zhou J, Hurley TD, Weiner H
Title	Human liver mitochondrial aldehyde dehydrogenase: three-dimensional structure and the restoration of solubility and activity of chimeric forms.
Related PDB
Related UniProtKB
[9]
Resource
Comments
Medline ID
PubMed ID	11104673
Journal	Biochem J
Year	2000
Volume	352
Pages	675-83
Authors	Velasco-Garcia R, Gonzalez-Segura L, Munoz-Clares RA
Title	Steady-state kinetic mechanism of the NADP+- and NAD+-dependent reactions catalysed by betaine aldehyde dehydrogenase from Pseudomonas aeruginosa.
Related PDB
Related UniProtKB

Comments
This enzyme belongs to aldehyde dehydrogenase family. This enzyme is homologous to other aldehyde dehydrogenases (D00020, D00022, D00475 and D00614). This dehydrogenase family shares a nucleophilic cysteine residue at the active site. During the reactions, the conformations of Glu263 and NAD may change, showing two different conformers, a passive mode and active mode (see [6]). According to the literature [2], [3], [5], [6], this enzyme catalyzes the following reactions: (A) Addition of nucleophilic cysteine residue to carbonyl carbon of substrate, forming a thiohemiacetal intermediate (I00156): (A0) Glu263 may act as a general base to activate Cys297. At least, Glu263 may have to deprotonate Cys297 indirectly through a water molecule. (A1) Cys297 makes a nucleophilic attack on the carbonyl carbon of substrate aldehyde, forming a covalent bond with it. This reaction leads to the formation of a thiohemiacetal intermediate (I00156). (A2) The oxyanion of the intermediate can be stabilized by the sidechain of Asn166 and the mainchain amide of Cys297. (B) Hydride transfer from the thiohemiacetal intermediate (I00156) to nicotinamide of NAD, forming a thioacyl intermediate (I00154): (B0) The oxyanion may be stabilized by Asn166 and the mainchain amide of Cys297. (B1) Hydride transfer from carbon atom of the nicotinamide of NAD. This reaction leads to formation of thioacyl intermediate (I00154). (C) Hydrolysis of the thioacyl intermediate (I00154): (C1) Glu263 acts as a general base to activate a water molecule. (C2) The activated water makes a nucleophilic attack on the thioacyl carbon of the intermediate (I00154). This reaction leads to formation of a tetrahedral intermediate (I00155). The oxyanion of the intermediate can be stabilized by the sidechain of Asn166 and the mainchain of Cys297. (C3) Finally, Cys297 is eliminated from the intermediate (I00155). Glu263 may protonate leaving Cys297 through a water.

Comments

This enzyme belongs to aldehyde dehydrogenase family. This enzyme is homologous to other aldehyde dehydrogenases (D00020, D00022, D00475 and D00614).
This dehydrogenase family shares a nucleophilic cysteine residue at the active site.
During the reactions, the conformations of Glu263 and NAD may change, showing two different conformers, a passive mode and active mode (see [6]).
According to the literature [2], [3], [5], [6], this enzyme catalyzes the following reactions:
(A) Addition of nucleophilic cysteine residue to carbonyl carbon of substrate, forming a thiohemiacetal intermediate (I00156):
(A0) Glu263 may act as a general base to activate Cys297. At least, Glu263 may have to deprotonate Cys297 indirectly through a water molecule.
(A1) Cys297 makes a nucleophilic attack on the carbonyl carbon of substrate aldehyde, forming a covalent bond with it. This reaction leads to the formation of a thiohemiacetal intermediate (I00156).
(A2) The oxyanion of the intermediate can be stabilized by the sidechain of Asn166 and the mainchain amide of Cys297.
(B) Hydride transfer from the thiohemiacetal intermediate (I00156) to nicotinamide of NAD, forming a thioacyl intermediate (I00154):
(B0) The oxyanion may be stabilized by Asn166 and the mainchain amide of Cys297.
(B1) Hydride transfer from carbon atom of the nicotinamide of NAD. This reaction leads to formation of thioacyl intermediate (I00154).
(C) Hydrolysis of the thioacyl intermediate (I00154):
(C1) Glu263 acts as a general base to activate a water molecule.
(C2) The activated water makes a nucleophilic attack on the thioacyl carbon of the intermediate (I00154). This reaction leads to formation of a tetrahedral intermediate (I00155). The oxyanion of the intermediate can be stabilized by the sidechain of Asn166 and the mainchain of Cys297.
(C3) Finally, Cys297 is eliminated from the intermediate (I00155). Glu263 may protonate leaving Cys297 through a water.

Created	Updated
2004-03-16	2012-10-24