SASDCH2: Aldehyde dehydrogenase 7A1 (Aldehyde dehydrogenase 7A1 (Alpha-ami...

Basic information

• Entry: Database: SASBDB / ID: SASDCH2

Sample

Aldehyde dehydrogenase 7A1

• Aldehyde dehydrogenase 7A1 (Alpha-aminoadipic semialdehyde dehydrogenase) (protein), ALDH7A1, Homo sapiens

Function / homology

Function:

lysine catabolic process / L-aminoadipate-semialdehyde dehydrogenase / L-aminoadipate-semialdehyde dehydrogenase activity / Choline catabolism / choline catabolic process / Lysine catabolism / betaine-aldehyde dehydrogenase / betaine-aldehyde dehydrogenase (NAD+) activity / glycine betaine biosynthetic process from choline / aldehyde metabolic process / glyceraldehyde-3-phosphate dehydrogenase (NAD+) (non-phosphorylating) activity / aldehyde dehydrogenase (NAD+) / aldehyde dehydrogenase (NAD+) activity / sensory perception of sound / mitochondrial matrix / mitochondrion / extracellular exosome / identical protein binding / nucleus / cytosol

Domain/homology:

Aldehyde dehydrogenase family 7 member A1-like / Aldehyde dehydrogenase, glutamic acid active site / Aldehyde dehydrogenases glutamic acid active site. / Aldehyde dehydrogenase domain / Aldehyde dehydrogenase family / Aldehyde dehydrogenase, C-terminal / Aldehyde dehydrogenase, N-terminal / Aldehyde/histidinol dehydrogenase

Component:

Alpha-aminoadipic semialdehyde dehydrogenase

• Biological species: Homo sapiens (human)
• Citation: Journal: Biochemistry / Year: 2015; Title: Structural Basis of Substrate Recognition by Aldehyde Dehydrogenase 7A1.; Authors: Min Luo / John J Tanner / ; Abstract: Aldehyde dehydrogenase 7A1 (ALDH7A1) is part of lysine catabolism and catalyzes the NAD(+)-dependent oxidation of α-aminoadipate semialdehyde to α-aminoadipate. Herein, we describe a structural study of human ALDH7A1 focused on substrate recognition. Five crystal structures and small-angle X-ray scattering data are reported, including the first crystal structure of any ALDH7 family member complexed with α-aminoadipate. The product binds with the ε-carboxylate in the oxyanion hole, the aliphatic chain packed into an aromatic box, and the distal end of the product anchored by electrostatic interactions with five conserved residues. This binding mode resembles that of glutamate bound to the proline catabolic enzyme ALDH4A1. Analysis of ALDH7A1 and ALDH4A1 structures suggests key interactions that underlie substrate discrimination. Structures of apo ALDH7A1 reveal dramatic conformational differences from the product complex. Product binding is associated with a 16 Å movement of the C-terminus into the active site, which stabilizes the active conformation of the aldehyde substrate anchor loop. The fact that the C-terminus is part of the active site was hitherto unknown. Interestingly, the C-terminus and aldehyde anchor loop are disordered in a new tetragonal crystal form of the apoenzyme, implying that these parts of the enzyme are highly flexible. Our results suggest that the active site of ALDH7A1 is disassembled when the aldehyde site is vacant, and the C-terminus is a mobile element that forms quaternary structural interactions that aid aldehyde binding. These results are relevant to the c.1512delG genetic deletion associated with pyridoxine-dependent epilepsy, which alters the C-terminus of ALDH7A1.

Contact author

• John Tanner (Mizzou, University of Missouri-Columbia, Columbia, MO, USA)

Models

• Model #771: ; Type: atomic / Software: FoXS / Radius of dummy atoms: 1.90 A / Comment: chains A, B, C, and D of PDB 4ZUK; Search similar-shape structures of this assembly by Omokage search (details)

Sample

• Sample: Name: Aldehyde dehydrogenase 7A1
• Buffer: Name: 50 mM Tris, 5% glycerol, 0.5 mM tris(3-hydroxypropyl)phosphine, 50 mM NaCl; pH: 7.8

Entity #427

Name: ALDH7A1 / Type: protein
Description: Aldehyde dehydrogenase 7A1 (Alpha-aminoadipic semialdehyde dehydrogenase)
Formula weight: 55.56 / Num. of mol.: 4 / Source: Homo sapiens / References: UniProt: P49419-2
Sequence:

GHMSTLLINQ PQYAWLKELG LREENEGVYN GSWGGRGEVI TTYCPANNEP IARVRQASVA DYEETVKKAR EAWKIWADIP APKRGEIVRQ IGDALREKIQ VLGSLVSLEM GKILVEGVGE VQEYVDICDY AVGLSRMIGG PILPSERSGH ALIEQWNPVG LVGIITAFNF PVAVYGWNNA IAMICGNVCL WKGAPTTSLI SVAVTKIIAK VLEDNKLPGA ICSLTCGGAD IGTAMAKDER VNLLSFTGST QVGKQVGLMV QERFGRSLLE LGGNNAIIAF EDADLSLVVP SALFAAVGTA GQRCTTARRL FIHESIHDEV VNRLKKAYAQ IRVGNPWDPN VLYGPLHTKQ AVSMFLGAVE EAKKEGGTVV YGGKVMDRPG NYVEPTIVTG LGHDASIAHT ETFAPILYVF KFKNEEEVFA WNNEVKQGLS SSIFTKDLGR IFRWLGPKGS DCGIVNVNIP TSGAEIGGAF GGEKHTGGGR ESGSDAWKQY MRRSTCTINY SKDLPLAQGI KFQ

Experimental information

• Beam: Instrument name: Advanced Light Source (ALS) 12.3.1 (SIBYLS); City: Berkeley, CA / 国: USA / Type of source: X-ray synchrotron
• Detector: Name: MAR 165 CCD

Scan

Title: ALDH7A1 / Measurement date: Mar 9, 2014 / Unit: 1/A /

	Min	Max
Q	0.0094	0.3189

Distance distribution function P(R)

Sofotware P(R): GNOM 5.0 / Number of points: 351 /

	Min	Max
Q	0.014291	0.227123
P(R) point	1	351
R	0	115

Result

Type of curve: single_conc
Comments: The FoXS fits have χ values of 1.5 for the tetramer, 12.4 for the dimer, and 1.2 for the 96%/4% tetramer/dimer ensemble.

	Experimental	Porod
MW	222.2 kDa	-
Volume	-	270 nm3

	P(R)	P(R) error	Guinier	Guinier error
Forward scattering, I0	848	4	853	10
Radius of gyration, Rg	3.71 nm	0.01	3.77 nm	0.05

	Min	Max	Error
D	-	11.5	0.5
Guinier point	1	40	-