4-Hydroxyphenylpyruvate dioxygenase
4-hydroxyphenylpyruvate dioxygenase | |||||||||
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ExPASy NiceZyme view | | ||||||||
KEGG | KEGG entry | ||||||||
MetaCyc | metabolic pathway | ||||||||
PRIAM | profile | ||||||||
PDB structures | RCSB PDB PDBe PDBsum | ||||||||
Gene Ontology | AmiGO / QuickGO | ||||||||
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4-hydroxyphenylpyruvate dioxygenase | |||||||
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Identifiers | |||||||
Symbol | HPPD | ||||||
Alt. symbols | HPD; PPD | ||||||
Chr. 12 q24-qter | |||||||
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4-Hydroxyphenylpyruvate dioxygenase (HPPD), also known as α-ketoisocaproate dioxygenase (KIC dioxygenase), is an
β-hydroxy β-methylbutyrate.[2][3] HPPD is an enzyme that is found in nearly all aerobic forms of life.[4]
Enzyme mechanism
HPPD is categorized within a class of oxygenase enzymes that usually utilize
aromatic ring hydroxylation. The NIH-shift, which has been demonstrated through isotope-labeling studies, involves migration of an alkyl group to form a more stable carbocation
. The shift, accounts for the observation that C3 is bonded to C4 in 4-hydroxyphenylpyruvate but to C5 in homogentisate. The predicted mechanism of HPPD can be seen in the following figure:
Structure
HPPD is an enzyme that usually bonds to form tetramers in bacteria and dimers in
beta sheets (with the exception of the C-terminal helix). While even less is known about the function of the N-terminus of the enzyme, scientists have discovered that a single amino acid change in the N-terminal region can cause the disease known as hawkinsinuria.[12]
Function
In nearly all aerobic beings, 4-hydroxyphenylpyruvate dioxygenase is responsible for converting
fumarate.[14] While the overall products of this cycle are used to create energy, plants and higher order eukaryotes utilize HPPD for a much more important reason. In eukaryotes, HPPD is used to regulate blood tyrosine levels, and plants utilize this enzyme to help produce the cofactors plastoquinone and tocopherol which are essential for the plant to survive.[15]
Disease relevance
HPPD can be linked to one of the oldest known inherited metabolic disorders known as
Type III tyrosinemia[17] When the active HPPD enzyme concentration is low in the human body, it results in high levels of tyrosine concentration in the blood, which can cause mild mental retardation at birth, and degradation in vision as a patient grows older.[18]
In
HPPD inhibitors hypothesized that inhibiting HPPD and controlling tyrosine in the diet could treat this disease. A series of small clinical trials were attempted with one of their compounds, nitisinone were conducted and were successful, leading to nitisinone being brought to market as an orphan drug.[20][21]
Industrial relevance
Due to HPPD’s role in producing necessary cofactors in plants, there are several marketed
herbicides that block activity of this enzyme, and research underway to find new ones.[22]
References
- ^ "Homo sapiens: 4-hydroxyphenylpyruvate dioxygenase reaction". MetaCyc. SRI International. 20 August 2012. Retrieved 6 June 2016.
- ISBN 9780123877840. Retrieved 6 June 2016.
- PMID 14730970.
- S2CID 85784668.
- PMID 15581571.
- PMID 1158879.
- PMID 873932.
- PMID 3298972.
- PMID 15301540.
- PMID 10467142.
- PMID 11073718.
- .
- PMID 14886367.
- ISBN 978-0-08-024922-3.
- PMID 8784780.
- PMID 11073718.
- S2CID 19425434.
- ^ National Organization for Rare Disorders. Physician’s Guide to Tyrosinemia Type 1 Archived 2014-02-11 at the Wayback Machine
- S2CID 6717818.
- ^ "Nitisinone (Oral Route) Description and Brand Names -". Mayo Clinic.
- doi:10.1564/20feb09.
Further reading
- Saito I, Chujo Y, Shimazu H, Yamane M, Matsuura T (Sep 1975). "Nonenzymic oxidation of p-hydroxyphenylpyruvic acid with singlet oxygen to homogentisic acid. A model for the action of p-hydroxyphenylpyruvate hydroxylase". Journal of the American Chemical Society. 97 (18): 5272–7. PMID 1165361.
- Wada GH, Fellman JH, Fujita TS, Roth ES (Sep 1975). "Purification and properties of avian liver p-hydroxyphenylpyruvate hydroxylase". The Journal of Biological Chemistry. 250 (17): 6720–6. PMID 1158879.
- Johnson-Winters K, Purpero VM, Kavana M, Nelson T, Moran GR (Feb 2003). "(4-Hydroxyphenyl)pyruvate dioxygenase from Streptomyces avermitilis: the basis for ordered substrate addition". Biochemistry. 42 (7): 2072–80. PMID 12590595.