http://www.uniprot.org/uniprot/P08559
EC=1.2.4.1
Alternative name(s):
PDHE1-A type I
Gene names
Name: PDHA1
Synonyms: PHE1A
Sequence length 390 AA.
Sequence status Complete.
Sequence processing The displayed sequence is further processed into a mature form.
Protein existence Evidence at protein level
General annotation (Comments)
Function
The pyruvate dehydrogenase complex catalyzes the overall conversion of pyruvate to acetyl-CoA and CO2. It contains multiple copies of three enzymatic components: pyruvate dehydrogenase (E1), dihydrolipoamide acetyltransferase (E2) and lipoamide dehydrogenase (E3).
Catalytic activity
Pyruvate + [dihydrolipoyllysine-residue acetyltransferase] lipoyllysine = [dihydrolipoyllysine-residue acetyltransferase] S-acetyldihydrolipoyllysine + CO2.
Cofactor
Thiamine pyrophosphate.
Enzyme regulation
E1 activity is regulated by phosphorylation (inactivation) and dephosphorylation (activation) of the alpha subunit. Ref.29 Ref.30
Subunit structure
Tetramer of 2 alpha and 2 beta subunits.
Subcellular location
Mitochondrion matrix.
Tissue specificity
Ubiquitous.
Post-translational modification
Phosphorylation at Ser-293 by PDK family kinases blocks the access to active site, and inactivates the enzyme.
Involvement in disease
Defects in PDHA1 are a cause of pyruvate dehydrogenase E1-alpha deficiency (PDHAD) [MIM:312170]. An enzymatic defect causing primary lactic acidosis in children. It is associated with a broad clinical spectrum ranging from fatal lactic acidosis in the newborn to chronic neurologic dysfunction with structural abnormalities in the central nervous system without systemic acidosis. Ref.31 Ref.32 Ref.33 Ref.34 Ref.36 Ref.37 Ref.38 Ref.40 Ref.41 Ref.42 Ref.43 Ref.44 Ref.45 Ref.47
Defects in PDHA1 are the cause of X-linked Leigh syndrome (X-LS) [MIM:308930]. X-LS is an early-onset progressive neurodegenerative disorder with a characteristic neuropathology consisting of focal, bilateral lesions in one or more areas of the central nervous system, including the brainstem, thalamus, basal ganglia, cerebellum, and spinal cord. The lesions are areas of demyelination, gliosis, necrosis, spongiosis, or capillary proliferation. Clinical symptoms depend on which areas of the central nervous system are involved. The most common underlying cause is a defect in oxidative phosphorylation. LS may be a feature of a deficiency of any of the mitochondrial respiratory chain complexes.
