ACADSB: Human short/ branched chain acyl CoA dehydrogenase
Pike, A.C.W., Hozjan, V., Smee, C., Niesen, F.H., Kavanagh, K.L., Umeano, C., Turnbull, A.P., Gileadi, O., von Delft, F., Lee, W.H., Muller, S., Marsden, B.D., Bountra, C., Oppermann, U.
Datapack version: 1 (built on 27.Oct.08)
The enzyme short/branched chain acyl CoA dehydrogenase (ACADSB, ACAD7) catalyzes the α/β dehydrogenation of short/branched chain acyl CoAs like 2-methylbutyryl-CoA derived from isoleucine degradation to the corresponding enoyl-CoA ester (tiglyl-CoA). This constitutes the first step of a β-oxidation pathway leading to the final products propionyl-CoA and acetyl-CoA.
ACADSB is localized in mitochondria, and is a homotetrameric enzyme belonging to the FAD-dependent acyl-CoA dehydrogenase family. The electron acceptor in the reaction catalysed by ACAD enzymes is the electron transferring protein. ACADSB shows the greatest activity towards short/branched chain acyl CoAs, but can in addition metabolize straight-chain acyl CoA esters such as butyryl-CoA or hexanoyl CoAs. ACADSB may also be involved in controlling the metabolic flux of the anticonvulsive drug valproic acid, thus contributing to the toxicity profile of this compound, which includes liver damage (microvesicular steatosis) and induction of oxidative stress.
Defects in ACADSB are the cause of a poorly defined short/branched-chain acyl-CoA dehydrogenase deficiency (also called 2-methylbutyryl-CoA dehydrogenase deficiency or 2-methylbutyryl glycinuria). This is an autosomal recessive disorder of L-isoleucine catabolism and is characterized by an increase of 2-methylbutyrylglycine and 2-methylbutyrylcarnitine in blood and urine. Affected individuals have seizures and psychomotor delay as the main clinical features.
Human ACAD7, like other ACADs such as medium-chain acyl CoA dehydrogenase (MCAD) or rat ACADS, adopts a
tetrameric quarternary structure
composed of four identical monomeric subunits. The main
is governed completely by
from the C-terminal domains of each subunit (see below). The human structure
determined in this study
(PDB ID 2JIF) is
short-chain acyl-CoA dehydrogenase
structure previously determined by us from human (see
ACADS SGC webpage
; PDB 2VIG); or
(1JQI, ref 1); the monomeric subunits of the human structures can be overlaid with an rmsd of 1.0 Å (icb 11, 12). The monomer itself is built up of
three distinct domains
N-terminal, 6-helical domain
, a central
β-sheet of seven strands
C-terminal domain composed of 5 helices
(TIP 1: the background colour can be changed to
reset the view
FAD cofactor binding:
(green carbon atoms, electron density contoured at 1 sigma) is bound to each monomer, in a manner that the isoalloxazine ring is buried close to the active site, whereas the adenine portion is located in the interface formed between the C-terminal domains of the subunits forming the dimer, and the beta sheet of the subunit that also contains the isoalloxazine ring. Even one residue of the third subunit, Gln330 engages in adenine contacts.
, the pyrophosphate forms contacts to Ser183 main-chain (
), and Arg319 (
) as well as the amide of Gly391 (
). The isoalloxazine ring is buried into a partially hydrophobic cleft, and forms hydrogen bonding contacts to main-chain atoms of residues Phe174, Leu176, Ser177 and Ser209 (
Cocrystallization of ACADSB with a CoA molecule reveals that a possible
substrate (grey carbon atoms) would bind to
, in a manner that engages
only contacts from this subunit
. The adenine part of the substrate molecule is bound through a bidentate H-bond to Asn291, and the phosphopanthteine chain is held in place through main-chain interactions with Ser183 and through side-chain contacts of Arg294. The ribose phosphate group makes hydrogen bonding contacts to Tyr229 and Tyr283. The terminal portion of the CoA molecule extends into a
site around Glu414
, which has been identified as the catalytic acid/base in ACADS and related ACADs such as ACADSB. The location in the active site makes it perfectly suited for this catalytic role. The ACAD enzymes catalyze the α,β-dehydrogenation of acyl-CoA thioesters, in which an α-hydrogen is abstracted as a proton from the acyl-CoA thioester substrate with a β-hydrogen transferred as a hydride ion to the N(5) position of the enzyme-bound FAD (1, 2). The reduced ACAD is then reoxidized by the electron transfer flavoprotein in a series of two one-electron transfers (3-4).
The target annotations and structure descriptions within this datapack are compiled by our Principal Investigators and are not peer-reviewed. If you find anything in the annotations that is not accurate, please notify us using the our
on-line feedback page
or send an e-mail to
1. Battaile KP, Molin-Case J, Paschke R, Wang M, Bennett D, Vockley J, Kim JJ. Crystal structure of rat short chain acyl-CoA dehydrogenase complexed with acetoacetyl-CoA: comparison with other acyl-CoA dehydrogenases. J Biol Chem. 2002 Apr 5;277(14):12200-7.
2. Pohl B, Raichle T, Ghisla S. Studies on the reaction mechanism of general acyl-CoA dehydrogenase. Determination of selective isotope effects in the dehydrogenation of butyryl-CoA. Eur J Biochem. 1986 Oct 1;160(1):109-15.
3. Crane FL, Mii S, Hauge JG, Green DE, Beinert H.On the mechanism of dehydrogenation of fatty acyl derivatives of coenzyme A. I. The general fatty acyl coenzyme A dehydrogenase. J Biol Chem. 1956 Feb;218(2):701-6.
4. Crane FL, Beinert H. On the mechanism of dehydrogenation of fatty acyl derivatives of coenzyme A. II. The electron-transferring flavoprotein. J Biol Chem. 1956 Feb;218(2):717-31.
Download Standalone iSee datapack: You can download and view all the Information of a datapack offline including information not available in the web version (where applicable). You will also need to download and install the ICM-Browser to view the standalone datapacks.
Datapack created using Molsoft ICM and Molsoft Browser technologies. (Patent Pending)