関: HPPD

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2014/07/07 21:35:08」(JST)

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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

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 it only utilizes 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

Proposed Reaction Mechanism of HPPD

Enzyme Structure

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 composed entirely of residues near the C-terminus of the enzyme. The active site of HPPD 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

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

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]

In Type I tyrosinemia, a different enzyme, fumarylacetoacetate hydrolase is mutated and doesn't work, leading to very harmful products building up in the body.^[16] Fumarylacetoacetate hydrolase acts on tyrosine after HPPD does, so scientists working on making herbicides in the class of 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.^[17]^[18]^[19]

Industrial relevance

Due to HPPD’s role in producing necessary cofactors in plants, there has been a large amount of research done to produce HPPD inhibitor herbicides that block activity of this enzyme.

References

^ Fritze, I.M.; Freigang, J., Auerbach, G., Huber, R., Steinbacher, S. (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. ; rendered with UCSF Chimera [1]
^ 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. doi:10.1021/bi035762w.
^ 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
^ Moran GR. 4-Hydroxyphenylpyruvate dioxygenase Arch Biochem Biophys. 2005 Jan 1;433(1):117-28. PMID 15581571
^ 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.
^ 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.
^ Buckthal, D. J., Roche, P. A., Moorehead, T. J., Forbes, B. J. R., & Hamilton, G. A. (1987). [18] 4-hydroxyphenylpyruvate dioxygenase from pig liver
^ 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. doi:10.1021/bi049323o.
^ 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. doi:10.1016/s0969-2126(99)80124-5.
^ 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. doi:10.1006/mgme.2000.3085.
^ Knox, W. E. (1955). [38] enzymes involved in conversion of tyrosine to acetoacetate. A. l-tyrosine-oxiding system of liver {black small square}
^ T.W. Goodwin, E.I. Mercer Introduction to Plant Biochemistry Pergamon Press, Sydney (1983)
^ E.A. Garrod Lancet, ii (1902), pp. 1616–1620
^ 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.
^ 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.
^ National Organization for Rare Disorders. Physician’s Guide to Tyrosinemia Type 1
^ Lock EA et al. From toxicological problem to therapeutic use: the discovery of the mode of action of 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC), its toxicology and development as a drug. J Inherit Metab Dis. 1998 Aug;21(5):498-506. PMID 9728330
^ http://www.mayoclinic.com/health/drug-information/DR601005
^ Sobi Orfadin® (nitisinone)

Saito, I; Chujo, Y; Shimazu, H; Yamane, M; Matsuura, T; Cahnmann, Hans J. (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. doi:10.1021/ja00851a042. PMID 1165361.
Wada, GH; Fellman, JH; Fujita, TS; Roth, ES (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 (2003). "(4-Hydroxyphenyl)pyruvate dioxygenase from Streptomyces avermitilis: the basis for ordered substrate addition". Biochemistry 42 (7): 2072–80. doi:10.1021/bi026499m. PMID 12590595.

UpToDate Contents

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English Journal

4-Hydroxyphenylpyruvate dioxygenase and hydroxymandelate synthase: Exemplars of the α-keto acid dependent oxygenases.

Moran GR.Author information Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, 3210 N. Cramer St, Milwaukee, WI 53211-3209, United States. Electronic address: moran@uwm.edu.Abstract4-Hydroxyphenylpyruvate dioxygenase (HPPD) and hydroxymandelate synthase (HMS) are outliers within the α-keto acid dependent oxygenase (αKAO) family. HPPD and HMS catalyze the chemistry of the majority of enzymes within the αKAO family but are clearly mechanistically convergent, having a grossly different structural topology. Some of the unique characteristics of HPPD and HMS have elucidated select parts of the catalytic cycle that are obscured in other family members. Moreover, the inhibitory chemistry of HPPD is a phenomenon with ever-expanding relevance across all kingdoms of life. This review is a synopsis of the literature pertaining to HPPD and HMS. It is not intended as an exhaustive compilation of all observations made for these enzymes but rather a condensed narrative that connects those studies that have advanced the understanding of the chemistry of both enzymes.
Archives of biochemistry and biophysics.Arch Biochem Biophys.2013 Nov 6. pii: S0003-9861(13)00342-1. doi: 10.1016/j.abb.2013.10.022. [Epub ahead of print]
4-Hydroxyphenylpyruvate dioxygenase (HPPD) and hydroxymandelate synthase (HMS) are outliers within the α-keto acid dependent oxygenase (αKAO) family. HPPD and HMS catalyze the chemistry of the majority of enzymes within the αKAO family but are clearly mechanistically convergent, having a grossly
PMID 24211436

The discovery of 3-(1-aminoethylidene)quinoline-2, 4(1H,3H)-dione derivatives as novel PSII electron transport inhibitors.

Liu YX, Zhao HP, Wang ZW, Li YH, Song HB, Riches H, Beattie D, Gu YC, Wang QM.Author information State Key Laboratory of Elemento-Organic Chemistry, Research Institute of Elemento-Organic Chemistry, Nankai University, Tianjin, 300071, People's Republic of China.AbstractBased on the structures of the 4-hydroxyphenylpyruvate dioxygenase inhibitor mesotrione and natural product fischerellin A, a series of imine derivatives of (E)-3-acyl-quinoline-2,4(1H,3H)-dione (6, 12 and 16) were designed, synthesized and systematically evaluated for their herbicidal activity. The bioassay results indicated that most of the synthesized compounds displayed good to excellent herbicidal activity, of which 6e, 6g, 6h, 6q and 6t exhibited more than 50 % inhibition against Brassica napus L., Amaranthus retroflexu or Digitaria adscendens at a dosage of 94 g ha−1 or lower. The symptom of injured leaves in vivo, the high Hill reaction inhibitory activity of 6h in vitro(IC50 0.1μgmL−1) and the computer-based binding model of compound 6h with D1 protein in photosystem II (PSII) reaction centre suggest this novel structure to likely be a new type of PSII electron transport inhibitor. Thus, we have found a novel type of diketone enamine structure targeted at the PSII reaction centre.
Molecular diversity.Mol Divers.2013 Nov;17(4):701-10. doi: 10.1007/s11030-013-9466-6. Epub 2013 Aug 14.
Based on the structures of the 4-hydroxyphenylpyruvate dioxygenase inhibitor mesotrione and natural product fischerellin A, a series of imine derivatives of (E)-3-acyl-quinoline-2,4(1H,3H)-dione (6, 12 and 16) were designed, synthesized and systematically evaluated for their herbicidal activity. The
PMID 23943353

Intermediate partitioning kinetic isotope effects for the NIH shift of 4-hydroxyphenylpyruvate dioxygenase and the hydroxylation reaction of hydroxymandelate synthase reveal mechanistic complexity.

Shah DD, Conrad JA, Moran GR.Author information Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee , 3210 North Cramer Street, Milwaukee, Wisconsin 53211-3209, United States.Abstract4-Hydroxyphenylpyruvate dioxygenase (HPPD) and hydroxymandelate synthase (HMS) are similar enzymes that catalyze complex dioxygenation reactions using the substrates 4-hydroxyphenylpyruvate (HPP) and dioxygen. Both enzymes decarboxylate HPP and then hydroxylate the resulting hydroxyphenylacetate (HPA). The hydroxylation reaction catalyzed by HPPD displaces the aceto substituent of HPA in a 1,2-shift to form 2,5-dihydroxyphenylacetate (homogentisate, HG), whereas the hydroxylation reaction of HMS places a hydroxyl on the benzylic carbon forming 3'-hydroxyphenylacetate (S-hydroxymandelate, HMA) without ensuing chemistry. The wild-type form of HPPD and variants of both enzymes uncouple to form both native and non-native products. We have used intermediate partitioning to probe bifurcating steps that form these products by substituting deuteriums for protiums at the benzylic position of the HPP substrate. These substitutions result in altered ratios of products that can be used to calculate kinetic isotope effects (KIE) for the formation of a specific product. For HPPD, secondary normal KIEs indicate that cleavage of the bond in the displacement reaction prior to the shift occurs by a homolytic mechanism. NMR analysis of HG derived from HPPD reacting with enantiomerically pure R-3'-deutero-HPP indicates that no rotation about the bond to the radical occurs, suggesting that collapse of the biradical intermediate is rapid. The production of HMA was observed in HMS and HPPD variant reactions. HMS hydroxylates to form exclusively S-hydroxymandelate. When HMS is reacted with R-3'-deutero-HPP, the observed kinetic isotope effect represents geometry changes in the initial transition state for the nonabstracted proton. These data show evidence of sp(3) hybridization in a HPPD variant and sp(2) hybridization in HMS variants, suggesting that HMS stabilizes a more advanced transition state in order to catalyze H-atom abstraction.
Biochemistry.Biochemistry.2013 Sep 3;52(35):6097-107. doi: 10.1021/bi400534q. Epub 2013 Aug 20.
4-Hydroxyphenylpyruvate dioxygenase (HPPD) and hydroxymandelate synthase (HMS) are similar enzymes that catalyze complex dioxygenation reactions using the substrates 4-hydroxyphenylpyruvate (HPP) and dioxygen. Both enzymes decarboxylate HPP and then hydroxylate the resulting hydroxyphenylacetate (HP
PMID 23941465

Japanese Journal

4-ヒドロキシフェニルピルビン酸ジオキシゲナーゼの特徴に注目した阻害剤の構造と簡易的阻害活性試験法

日本農薬学会誌 39(1), 78-82, 2014
NAID 130005002072

新規除草剤トプラメゾン液剤による飼料用トウモロコシ畑の外来雑草10種に対する除草効果とオオブタクサ防除における実用上の課題

雑草研究 58(2), 69-75, 2012
NAID 130004504077

Hepatorenal tyrosinemia

Proceedings of the Japan Academy, Series B 88(5), 192-200, 2012
NAID 130001924745

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リンク元	「HPPD」「4-ヒドロキシフェニルピルビン酸ジオキシゲナーゼ」
関連記事	「dioxygenase」

「HPPD」

4-hydroxyphenylpyruvate dioxygenase
Identifiers
Symbol	HPPD
Alt. symbols	HPD; PPD
Entrez	3242
HUGO	5147
OMIM	609695
RefSeq	NM_002150
UniProt	P32754
Other data
Locus	Chr. 12 q24-qter

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PubMed	articles
NCBI	proteins

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
Identifiers
EC number	1.13.11.27
CAS number	9029-72-5
Databases
IntEnz	IntEnz view
BRENDA	BRENDA entry
ExPASy	NiceZyme view
KEGG	KEGG entry
MetaCyc	metabolic pathway
PRIAM	profile
PDB structures	RCSB PDB PDBe PDBsum
Gene Ontology	AmiGO / EGO
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PubMed	articles
NCBI	proteins