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4-hydroxyphenylpyruvate dioxygenase
Homodimer of 4-Hydroxyphenylpyruvate dioxygenase. Red ribbon represents iron-containing catalytic domain (with Fe 2+ represented as red-orange spheres); blue represents the oligomeric domain. Image generated from published structural data [1]
Identifiers
EC no.1.13.11.27
CAS no.9029-72-5
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO
Search
PMCarticles
PubMedarticles
NCBIproteins
4-hydroxyphenylpyruvate dioxygenase
Identifiers
SymbolHPPD
Alt. symbolsHPD; PPD
NCBI gene3242
HGNC5147
OMIM609695
RefSeqNM_002150
UniProtP32754
Other data
EC number1.13.11.27
LocusChr. 12 q24-qter
Search for
StructuresSwiss-model
DomainsInterPro


4- Hydroxyphenylpyruvate dioxygenase (HPPD) is an Fe(II)-containing non-heme oxygenase that catalyzes the second reaction in the catabolism of tyrosine - the conversion of 4-hydroxyphenylpyruvate into homogentisate. HPPD is an enzyme that is found in nearly all aerobic forms of life [2]. The reaction that HPPD achieves is shown here

HPPD Reaction


Enzyme Mechanism edit

HPPD is categorized within a class of oxygenase enzymes that usually utilize α-ketoglutarate and diatomic oxygen to oxygenate or oxidize a target molecule [3]. However, HPPD differs from most molecules in this class due to the fact that it does not use α-ketoglutarate, and only utilizing two substrates while adding both atoms of diatomic oxygen into the product, homogentisate [4]. The HPPD reaction occurs through a NIH shift and involves the oxidative decarboxylation of an α-oxo acid as well as 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


Enzyme Structure edit

HPPD is an enzyme that usually bonds to form tetramers in bacteria and dimers in eukaryotes and has a subunit mass of 40-50 kDa.[5][6][7] Dividing the enzyme into the N-terminus and C-terminus one will notice that the N-terminus varies in composition while the C-terminus remains relatively constant[8] (the C-terminus in plants does differ slightly from the C-terminus in other beings). In 1999 the first X-ray crystallography structure of HPPD was created[9]and since then it has been discovered that the active site of HPPD is comprised entirely of residues near the C-terminus of the enzyme. The active site of HPPD is has not been completely mapped, but it is known that the site consists of an iron ion surrounded by amino acids extending inward from 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.[10]

Biologic Function edit

In nearly all aerobic beings, 4- Hydroxyphenylpyruvate dioxygenase is responsible for converting 4- Hydroxyphenylpyruvate into homogentisate. This conversion is one of many steps in breaking L-tyrosine into acetoacetate and fumarate.[11] 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.[12]

Disease Relevance edit

HPPD can be linked to one of the oldest known inherited metabolic disorders known as alkaptonuria, which is caused by low levels of homogentisate in the blood stream.[13] HPPD is also directly linked to Type III tyrosinemia[14] 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.[15]

Industrial Relevance edit

Due to HPPD’s role in producing necessary cofactors in plants, there has been a large amount of research done to produce herbicides that inhibit its function.



References edit

  1. ^ Fritze, Iris M.; Linden, Lars; Freigang, Jörg; Auerbach, GüNter; Huber, Robert; Steinbacher, Stefan (2004). "The Crystal Structures of Zea mays and Arabidopsis 4-Hydroxyphenylpyruvate Dioxygenase". Plant Physiol. 134 (4): 1388–1400. doi:10.1104/pp.103.034082. PMC 419816. PMID 15084729.{{cite journal}}: CS1 maint: date and year (link); rendered with UCSF Chimera [1]
  2. ^ Gunsior, M., Ravel, J., Challis, G. L., & Townsend, C. A. (2004). Engineering p-hydroxyphenylpyruvate dioxygenase to a p-hydroxymandelate synthase and evidence for the proposed benzene oxide intermediate in homogentisate formation. Biochemistry, 43(3), 663-674.
  3. ^ Hausinger, Robert (2004). “Fe(II)/α-Ketoglutarate-Dependent Hydroxylases and Related Enzymes.” Critical Reviews in Biochemistry and Molecular Biology. 39(1) 21-68. http://informahealthcare.com/doi/abs/10.1080/10409230490440541
  4. ^ Graham R. Moran, “4-Hydroxyphenylpyruvate dioxygenase”. Archives of Biochemistry and Biophysics, Volume 433, Issue 1, 1 January 2005, Pages 117-128, ISSN 0003-9861, 10.1016/j.abb.2004.08.015. (http://www.sciencedirect.com/science/article/pii/S000398610400459X)
  5. ^ Wada, G. H., Fellman, J. H., Fujita, T. S., & Roth, E. S. (1975). Purification and properties of avian liver p hydroxyphenylpyruvate hydroxylase. Journal of Biological Chemistry, 250(17), 6720-6726.
  6. ^ Lindblad, B., Lindstedt, G., Lindstedt, S., & Rundgren, M. (1977). Purification and some properties of human 4 hydroxyphenylpyruvate dioxygenase (I). Journal of Biological Chemistry, 252(14), 5073-5084.
  7. ^ Buckthal, D. J., Roche, P. A., Moorehead, T. J., Forbes, B. J. R., & Hamilton, G. A. (1987). [18] 4-hydroxyphenylpyruvate dioxygenase from pig liver
  8. ^ Yang, C., Pflugrath, J. W., Camper, D. L., Foster, M. L., Pernich, D. J., & Walsh, T. A. (2004). Structural basis for herbicidal inhibitor selectivity revealed by comparison of crystal structures of plant and mammalian 4-hydroxyphenylpyruvate dioxygenases. Biochemistry, 43(32), 10414-10423.
  9. ^ Serre, L., Sailland, A., Sy, D., Boudec, P., Rolland, A., Pebay-Peyroula, E., et al. (1999). Crystal structure of pseudomonas fluorescens 4-hydroxyphenylpyruvate dioxygenase: An enzyme involved in the tyrosine degradation pathway. Structure, 7(8), 977-988.
  10. ^ Tomoeda, K., Awata, H., Matsuura, T., Matsuda, I., Ploechl, E., Milovac, T., et al. (2000). Mutations in the 4-hydroxyphenylpyruvic acid dioxygenase gene are responsible for tyrosinemia type III and hawkinsinuria. Molecular Genetics and Metabolism, 71(3), 506-510.
  11. ^ Knox, W. E. (1955). [38] enzymes involved in conversion of tyrosine to acetoacetate. A. l-tyrosine-oxiding system of liver {black small square}
  12. ^ T.W. Goodwin, E.I. Mercer Introduction to Plant Biochemistry Pergamon Press, Sydney (1983)
  13. ^ E.A. Garrod Lancet, ii (1902), pp. 1616–1620
  14. ^ Tomoeda, K., Awata, H., Matsuura, T., Matsuda, I., Ploechl, E., Milovac, T., et al. (2000). Mutations in the 4-hydroxyphenylpyruvic acid dioxygenase gene are responsible for tyrosinemia type III and hawkinsinuria. Molecular Genetics and Metabolism, 71(3), 506-510.
  15. ^ Hühn, R., Stoermer, H., Klingele, B., Bausch, E., Fois, A., Farnetani, M., et al. (1998). Novel and recurrent tyrosine aminotransferase gene mutations in tyrosinemia type II. Human Genetics, 102(3), 305-313.

Category:EC 1.13.11

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