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4-Hydroxyphenylpyruvate dioxygenase

August 20, 2023

4-Hydroxyphenylpyruvate dioxygenase (HPPD), also known as α-ketoisocaproate dioxygenase (KIC dioxygenase), 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 also catalyzes the conversion of phenylpyruvate to 2-hydroxyphenylacetate and the conversion of α-ketoisocaproate to β-hydroxy β-methylbutyrate.[2][3] HPPD is an enzyme that is found in nearly all aerobic forms of life.[4]

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
This reaction shows the conversion of 4-hydroxyphenylpyruvate into homogentisate by HPPD.

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.[5] 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.[6] 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

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.[7][8][9] 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[10] (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[11] 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.[12]

Function

In nearly all aerobic beings, 4-hydroxyphenylpyruvate dioxygenase is responsible for converting 4-hydroxyphenylpyruvate into homogentisate.[13] This conversion is one of many steps in breaking L-tyrosine into acetoacetate and 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 alkaptonuria, which is caused by high levels of homogentisate in the blood stream.[16] HPPD is also directly linked to 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 Type I tyrosinemia, a different enzyme, fumarylacetoacetate hydrolase is mutated and doesn't work, leading to very harmful products building up in the body.[19] 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.[20][21]

Industrial relevance

Due to HPPD’s role in producing necessary cofactors in plants, there are several marketed HPPD inhibitor herbicides that block activity of this enzyme, and research underway to find new ones.[22]

References

  1. ^ Fritze IM, Linden L, Freigang J, Auerbach G, Huber R, Steinbacher S (Apr 2004). "The crystal structures of Zea mays and Arabidopsis 4-hydroxyphenylpyruvate dioxygenase". Plant Physiology. 134 (4): 1388–400. doi:10.1104/pp.103.034082. PMC 419816. PMID 15084729.; rendered with UCSF Chimera [1]
  2. ^ "Homo sapiens: 4-hydroxyphenylpyruvate dioxygenase reaction". MetaCyc. SRI International. 20 August 2012. Retrieved 6 June 2016.
  3. ^ Kohlmeier M (2015). "Leucine". Nutrient Metabolism: Structures, Functions, and Genes (2nd ed.). Academic Press. pp. 385–388. ISBN 9780123877840. Retrieved 6 June 2016.
  4. ^ Gunsior M, Ravel J, Challis GL, Townsend CA (Jan 2004). "Engineering p-hydroxyphenylpyruvate dioxygenase to a p-hydroxymandelate synthase and evidence for the proposed benzene oxide intermediate in homogentisate formation". Biochemistry. 43 (3): 663–74. doi:10.1021/bi035762w. PMID 14730970.
  5. ^ Hausinger RP (2004). "FeII/alpha-ketoglutarate-dependent hydroxylases and related enzymes". Critical Reviews in Biochemistry and Molecular Biology. 39 (1): 21–68. doi:10.1080/10409230490440541. PMID 15121720. S2CID 85784668.
  6. ^ Moran GR (Jan 2005). "4-Hydroxyphenylpyruvate dioxygenase". Archives of Biochemistry and Biophysics. 433 (1): 117–28. doi:10.1016/j.abb.2004.08.015. PMID 15581571.
  7. ^ 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. doi:10.1016/S0021-9258(19)40992-7. PMID 1158879.
  8. ^ Lindblad B, Lindstedt G, Lindstedt S, Rundgren M (Jul 1977). "Purification and some properties of human 4-hydroxyphenylpyruvate dioxygenase (I)". The Journal of Biological Chemistry. 252 (14): 5073–84. doi:10.1016/S0021-9258(17)40160-8. PMID 873932.
  9. ^ Buckthal DJ, Roche PA, Moorehead TJ, Forbes BJ, Hamilton GA (1987). "4-Hydroxyphenylpyruvate dioxygenase from pig liver". Methods in Enzymology. 142: 132–8. doi:10.1016/s0076-6879(87)42020-x. PMID 3298972.
  10. ^ Yang C, Pflugrath JW, Camper DL, Foster ML, Pernich DJ, Walsh TA (Aug 2004). "Structural basis for herbicidal inhibitor selectivity revealed by comparison of crystal structures of plant and mammalian 4-hydroxyphenylpyruvate dioxygenases". Biochemistry. 43 (32): 10414–23. doi:10.1021/bi049323o. PMID 15301540.
  11. ^ Serre L, Sailland A, Sy D, Boudec P, Rolland A, Pebay-Peyroula E, Cohen-Addad C (Aug 1999). "Crystal structure of Pseudomonas fluorescens 4-hydroxyphenylpyruvate dioxygenase: an enzyme involved in the tyrosine degradation pathway". Structure. 7 (8): 977–88. doi:10.1016/s0969-2126(99)80124-5. PMID 10467142.
  12. ^ Tomoeda K, Awata H, Matsuura T, Matsuda I, Ploechl E, Milovac T, Boneh A, Scott CR, Danks DM, Endo F (Nov 2000). "Mutations in the 4-hydroxyphenylpyruvic acid dioxygenase gene are responsible for tyrosinemia type III and hawkinsinuria". Molecular Genetics and Metabolism. 71 (3): 506–10. doi:10.1006/mgme.2000.3085. PMID 11073718.
  13. ^ Zea-Rey AV, Cruz-Camino H, Vazquez-Cantu DL, Gutiérrez-García VM, Santos-Guzmán J, Cantú-Reyna C (27 November 2017). "The Incidence of Transient Neonatal Tyrosinemia Within a Mexican Population" (PDF). Journal of Inborn Errors of Metabolism and Screening. 5: 232640981774423. doi:10.1177/2326409817744230.
  14. ^ Knox WE, LeMay-Knox M (October 1951). "The oxidation in liver of l-tyrosine to acetoacetate through p-hydroxyphenylpyruvate and homogentisic acid". The Biochemical Journal. 49 (5): 686–93. doi:10.1042/bj0490686. PMC 1197578. PMID 14886367.
  15. ^ Mercer E, Goodwin T (1988). Introduction to Plant Biochemistry (2nd ed.). Oxford: Pergamon Press. ISBN 978-0-08-024922-3.
  16. ^ Garrod EA (1902). "The incidence of alkaptonuria: a study in chemical individuality". Lancet. 160 (4134): 1616–1620. doi:10.1016/s0140-6736(01)41972-6. PMC 2230159. PMID 8784780.
  17. ^ Tomoeda K, Awata H, Matsuura T, Matsuda I, Ploechl E, Milovac T, Boneh A, Scott CR, Danks DM, Endo F (Nov 2000). "Mutations in the 4-hydroxyphenylpyruvic acid dioxygenase gene are responsible for tyrosinemia type III and hawkinsinuria". Molecular Genetics and Metabolism. 71 (3): 506–10. doi:10.1006/mgme.2000.3085. PMID 11073718.
  18. ^ Hühn R, Stoermer H, Klingele B, Bausch E, Fois A, Farnetani M, Di Rocco M, Boué J, Kirk JM, Coleman R, Scherer G (Mar 1998). "Novel and recurrent tyrosine aminotransferase gene mutations in tyrosinemia type II". Human Genetics. 102 (3): 305–13. doi:10.1007/s004390050696. PMID 9544843. S2CID 19425434.
  19. ^ National Organization for Rare Disorders. Physician’s Guide to Tyrosinemia Type 1 2014-02-11 at the Wayback Machine
  20. ^ Lock EA, Ellis MK, Gaskin P, Robinson M, Auton TR, Provan WM, Smith LL, Prisbylla MP, Mutter LC, Lee DL (Aug 1998). "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". Journal of Inherited Metabolic Disease. 21 (5): 498–506. doi:10.1023/A:1005458703363. PMID 9728330. S2CID 6717818.
  21. ^ "Nitisinone (Oral Route) Description and Brand Names -". Mayo Clinic.
  22. ^ van Almsick A (2009). "New HPPD-Inhibitors - A Proven Mode of Action as a New Hope to Solve Current Weed Problems". Outlooks on Pest Management. 20 (1): 27–30. 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. doi:10.1021/ja00851a042. 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. doi:10.1016/S0021-9258(19)40992-7. 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. doi:10.1021/bi026499m. PMID 12590595.

August 20, 2023
hydroxyphenylpyruvate, dioxygenase, hppd, also, known, ketoisocaproate, dioxygenase, dioxygenase, containing, heme, oxygenase, that, catalyzes, second, reaction, catabolism, tyrosine, conversion, hydroxyphenylpyruvate, into, homogentisate, hppd, also, catalyze. 4 Hydroxyphenylpyruvate dioxygenase HPPD also known as a ketoisocaproate dioxygenase KIC dioxygenase 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 also catalyzes the conversion of phenylpyruvate to 2 hydroxyphenylacetate and the conversion of a ketoisocaproate to b hydroxy b methylbutyrate 2 3 HPPD is an enzyme that is found in nearly all aerobic forms of life 4 4 hydroxyphenylpyruvate dioxygenaseHomodimer 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 IdentifiersEC no 1 13 11 27CAS no 9029 72 5DatabasesIntEnzIntEnz viewBRENDABRENDA entryExPASyNiceZyme viewKEGGKEGG entryMetaCycmetabolic pathwayPRIAMprofilePDB structuresRCSB PDB PDBe PDBsumGene OntologyAmiGO QuickGOSearchPMCarticlesPubMedarticlesNCBIproteins4 hydroxyphenylpyruvate dioxygenaseIdentifiersSymbolHPPDAlt symbolsHPD PPDNCBI gene3242HGNC5147OMIM609695RefSeqNM 002150UniProtP32754Other dataEC number1 13 11 27LocusChr 12 q24 qterSearch forStructuresSwiss modelDomainsInterPro This reaction shows the conversion of 4 hydroxyphenylpyruvate into homogentisate by HPPD Contents 1 Enzyme mechanism 2 Structure 3 Function 4 Disease relevance 5 Industrial relevance 6 References 7 Further readingEnzyme mechanism EditHPPD is categorized within a class of oxygenase enzymes that usually utilize a ketoglutarate and diatomic oxygen to oxygenate or oxidize a target molecule 5 However HPPD differs from most molecules in this class due to the fact that it does not use a ketoglutarate and it only utilizes two substrates while adding both atoms of diatomic oxygen into the product homogentisate 6 The HPPD reaction occurs through a NIH shift and involves the oxidative decarboxylation of an a 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 HPPDStructure EditHPPD is an enzyme that usually bonds to form tetramers in bacteria and dimers in eukaryotes and has a subunit mass of 40 50 kDa 7 8 9 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 10 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 11 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 12 Function EditIn nearly all aerobic beings 4 hydroxyphenylpyruvate dioxygenase is responsible for converting 4 hydroxyphenylpyruvate into homogentisate 13 This conversion is one of many steps in breaking L tyrosine into acetoacetate and 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 EditHPPD can be linked to one of the oldest known inherited metabolic disorders known as alkaptonuria which is caused by high levels of homogentisate in the blood stream 16 HPPD is also directly linked to 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 Type I tyrosinemia a different enzyme fumarylacetoacetate hydrolase is mutated and doesn t work leading to very harmful products building up in the body 19 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 20 21 Industrial relevance EditDue to HPPD s role in producing necessary cofactors in plants there are several marketed HPPD inhibitor herbicides that block activity of this enzyme and research underway to find new ones 22 References Edit Fritze IM Linden L Freigang J Auerbach G Huber R Steinbacher S Apr 2004 The crystal structures of Zea mays and Arabidopsis 4 hydroxyphenylpyruvate dioxygenase Plant Physiology 134 4 1388 400 doi 10 1104 pp 103 034082 PMC 419816 PMID 15084729 rendered with UCSF Chimera 1 Homo sapiens 4 hydroxyphenylpyruvate dioxygenase reaction MetaCyc SRI International 20 August 2012 Retrieved 6 June 2016 Kohlmeier M 2015 Leucine Nutrient Metabolism Structures Functions and Genes 2nd ed Academic Press pp 385 388 ISBN 9780123877840 Retrieved 6 June 2016 Gunsior M Ravel J Challis GL Townsend CA Jan 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 74 doi 10 1021 bi035762w PMID 14730970 Hausinger RP 2004 FeII alpha ketoglutarate dependent hydroxylases and related enzymes Critical Reviews in Biochemistry and Molecular Biology 39 1 21 68 doi 10 1080 10409230490440541 PMID 15121720 S2CID 85784668 Moran GR Jan 2005 4 Hydroxyphenylpyruvate dioxygenase Archives of Biochemistry and Biophysics 433 1 117 28 doi 10 1016 j abb 2004 08 015 PMID 15581571 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 doi 10 1016 S0021 9258 19 40992 7 PMID 1158879 Lindblad B Lindstedt G Lindstedt S Rundgren M Jul 1977 Purification and some properties of human 4 hydroxyphenylpyruvate dioxygenase I The Journal of Biological Chemistry 252 14 5073 84 doi 10 1016 S0021 9258 17 40160 8 PMID 873932 Buckthal DJ Roche PA Moorehead TJ Forbes BJ Hamilton GA 1987 4 Hydroxyphenylpyruvate dioxygenase from pig liver Methods in Enzymology 142 132 8 doi 10 1016 s0076 6879 87 42020 x PMID 3298972 Yang C Pflugrath JW Camper DL Foster ML Pernich DJ Walsh TA Aug 2004 Structural basis for herbicidal inhibitor selectivity revealed by comparison of crystal structures of plant and mammalian 4 hydroxyphenylpyruvate dioxygenases Biochemistry 43 32 10414 23 doi 10 1021 bi049323o PMID 15301540 Serre L Sailland A Sy D Boudec P Rolland A Pebay Peyroula E Cohen Addad C Aug 1999 Crystal structure of Pseudomonas fluorescens 4 hydroxyphenylpyruvate dioxygenase an enzyme involved in the tyrosine degradation pathway Structure 7 8 977 88 doi 10 1016 s0969 2126 99 80124 5 PMID 10467142 Tomoeda K Awata H Matsuura T Matsuda I Ploechl E Milovac T Boneh A Scott CR Danks DM Endo F Nov 2000 Mutations in the 4 hydroxyphenylpyruvic acid dioxygenase gene are responsible for tyrosinemia type III and hawkinsinuria Molecular Genetics and Metabolism 71 3 506 10 doi 10 1006 mgme 2000 3085 PMID 11073718 Zea Rey AV Cruz Camino H Vazquez Cantu DL Gutierrez Garcia VM Santos Guzman J Cantu Reyna C 27 November 2017 The Incidence of Transient Neonatal Tyrosinemia Within a Mexican Population PDF Journal of Inborn Errors of Metabolism and Screening 5 232640981774423 doi 10 1177 2326409817744230 Knox WE LeMay Knox M October 1951 The oxidation in liver of l tyrosine to acetoacetate through p hydroxyphenylpyruvate and homogentisic acid The Biochemical Journal 49 5 686 93 doi 10 1042 bj0490686 PMC 1197578 PMID 14886367 Mercer E Goodwin T 1988 Introduction to Plant Biochemistry 2nd ed Oxford Pergamon Press ISBN 978 0 08 024922 3 Garrod EA 1902 The incidence of alkaptonuria a study in chemical individuality Lancet 160 4134 1616 1620 doi 10 1016 s0140 6736 01 41972 6 PMC 2230159 PMID 8784780 Tomoeda K Awata H Matsuura T Matsuda I Ploechl E Milovac T Boneh A Scott CR Danks DM Endo F Nov 2000 Mutations in the 4 hydroxyphenylpyruvic acid dioxygenase gene are responsible for tyrosinemia type III and hawkinsinuria Molecular Genetics and Metabolism 71 3 506 10 doi 10 1006 mgme 2000 3085 PMID 11073718 Huhn R Stoermer H Klingele B Bausch E Fois A Farnetani M Di Rocco M Boue J Kirk JM Coleman R Scherer G Mar 1998 Novel and recurrent tyrosine aminotransferase gene mutations in tyrosinemia type II Human Genetics 102 3 305 13 doi 10 1007 s004390050696 PMID 9544843 S2CID 19425434 National Organization for Rare Disorders Physician s Guide to Tyrosinemia Type 1 Archived 2014 02 11 at the Wayback Machine Lock EA Ellis MK Gaskin P Robinson M Auton TR Provan WM Smith LL Prisbylla MP Mutter LC Lee DL Aug 1998 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 Journal of Inherited Metabolic Disease 21 5 498 506 doi 10 1023 A 1005458703363 PMID 9728330 S2CID 6717818 Nitisinone Oral Route Description and Brand Names Mayo Clinic van Almsick A 2009 New HPPD Inhibitors A Proven Mode of Action as a New Hope to Solve Current Weed Problems Outlooks on Pest Management 20 1 27 30 doi 10 1564 20feb09 Further reading EditSaito 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 doi 10 1021 ja00851a042 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 doi 10 1016 S0021 9258 19 40992 7 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 doi 10 1021 bi026499m PMID 12590595 Portal Biology Retrieved from https en wikipedia org w index php title 4 Hydroxyphenylpyruvate dioxygenase amp oldid 1166576826, wikipedia, wiki, book, books, library,

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