[English] 日本語
![](img/lk-miru.gif)
- SASDGL4: Human alpha-aminoadipic semialdehyde dehydrogenase (ALDH)7A1 E399... -
+
Open data
-
Basic information
Entry | Database: SASBDB / ID: SASDGL4 |
---|---|
![]() | Human alpha-aminoadipic semialdehyde dehydrogenase (ALDH)7A1 E399Q at 1.1 mg/mL
|
Function / homology | ![]() L-aminoadipate-semialdehyde dehydrogenase / L-aminoadipate-semialdehyde dehydrogenase activity / Choline catabolism / choline catabolic process / betaine-aldehyde dehydrogenase / betaine-aldehyde dehydrogenase (NAD+) activity / Lysine catabolism / cellular aldehyde metabolic process / glycine betaine biosynthetic process from choline / glyceraldehyde-3-phosphate dehydrogenase (NAD+) (non-phosphorylating) activity ...L-aminoadipate-semialdehyde dehydrogenase / L-aminoadipate-semialdehyde dehydrogenase activity / Choline catabolism / choline catabolic process / betaine-aldehyde dehydrogenase / betaine-aldehyde dehydrogenase (NAD+) activity / Lysine catabolism / cellular aldehyde metabolic process / glycine betaine biosynthetic process from choline / 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 Similarity search - Function |
Biological species | ![]() |
![]() | ![]() Title: Structural analysis of pathogenic mutations targeting Glu427 of ALDH7A1, the hot spot residue of pyridoxine-dependent epilepsy. Authors: Adrian R Laciak / David A Korasick / Kent S Gates / John J Tanner / ![]() Abstract: Certain loss-of-function mutations in the gene encoding the lysine catabolic enzyme aldehyde dehydrogenase 7A1 (ALDH7A1) cause pyridoxine-dependent epilepsy (PDE). Missense mutations of Glu427, ...Certain loss-of-function mutations in the gene encoding the lysine catabolic enzyme aldehyde dehydrogenase 7A1 (ALDH7A1) cause pyridoxine-dependent epilepsy (PDE). Missense mutations of Glu427, especially Glu427Gln, account for ~30% of the mutated alleles in PDE patients, and thus Glu427 has been referred to as a mutation hot spot of PDE. Glu427 is invariant in the ALDH superfamily and forms ionic hydrogen bonds with the nicotinamide ribose of the NAD cofactor. Here we report the first crystal structures of ALDH7A1 containing pathogenic mutations targeting Glu427. The mutant enzymes E427Q, Glu427Asp, and Glu427Gly were expressed in Escherichia coli and purified. The recombinant enzymes displayed negligible catalytic activity compared to the wild-type enzyme. The crystal structures of the mutant enzymes complexed with NAD were determined to understand how the mutations impact NAD binding. In the E427Q and E427G structures, the nicotinamide mononucleotide is highly flexible and lacks a defined binding pose. In E427D, the bound NAD adopts a "retracted" conformation in which the nicotinamide ring is too far from the catalytic Cys residue for hydride transfer. Thus, the structures revealed a shared mechanism for loss of function: none of the variants are able to stabilise the nicotinamide of NAD in the pose required for catalysis. We also show that these mutations reduce the amount of active tetrameric ALDH7A1 at the concentration of NAD tested. Altogether, our results provide the three-dimensional molecular structural basis of the most common pathogenic variants of PDE and implicate strong (ionic) hydrogen bonds in the aetiology of a human disease. |
![]() |
|
-
Structure visualization
Structure viewer | Molecule: ![]() ![]() |
---|
-
Downloads & links
-Data source
SASBDB page | ![]() |
---|
-Related structure data
-
External links
Related items in Molecule of the Month |
---|
-Models
Model #3615 | ![]() Type: atomic / Chi-square value: 0.833101006326262 ![]() |
---|---|
Model #3616 | ![]() Type: atomic / Chi-square value: 0.833101006326262 ![]() |
-
Sample
![]() | Name: Human alpha-aminoadipic semialdehyde dehydrogenase (ALDH)7A1 E399Q at 1.1 mg/mL Specimen concentration: 1.1 mg/ml |
---|---|
Buffer | Name: 50 mM HEPES, 100 mM NaCl, 1 mM DTT, 10 mM NAD, 5% (v/v) glycerol pH: 8 |
Entity #1842 | Name: ALDH7A1 E399Q / Type: protein Description: Alpha-aminoadipic semialdehyde dehydrogenase E399Q Formula weight: 55.559 / Source: Homo sapiens / References: UniProt: P49419 Sequence: GHMSTLLINQ PQYAWLKELG LREENEGVYN GSWGGRGEVI TTYCPANNEP IARVRQASVA DYEETVKKAR EAWKIWADIP APKRGEIVRQ IGDALREKIQ VLGSLVSLEM GKILVEGVGE VQEYVDICDY AVGLSRMIGG PILPSERSGH ALIEQWNPVG LVGIITAFNF ...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 QTFAPILYVF 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 ![]() | ||||||||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Detector | Name: Pilatus3 X 2M / Pixsize x: 172 mm | ||||||||||||||||||||||||||||||
Scan | Measurement date: May 1, 2019 / Storage temperature: 4 °C / Cell temperature: 10 °C / Unit: 1/A /
| ||||||||||||||||||||||||||||||
Result | Type of curve: single_conc /
|