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词条 Alpha-ketoglutarate-dependent hydroxylases
释义

  1. Biological function

  2. Catalytic mechanism

  3. Structure

     Protein  Metallocofactor  Substrate and cosubstrate binding 

  4. Inhibitors

  5. Assays

  6. References

{{cleanup HTML|date=February 2019}} Alpha-ketoglutarate-dependent hydroxylases are non-heme, iron-containing enzymes that consume oxygen and alpha-ketoglutarate (αKG, also known as 2-oxoglutarate, or 2OG) as co-substrates. They catalyse a wide range of oxygenation reactions. These include hydroxylation reactions, demethylations, ring expansions, ring closures and desaturations.[1][2] Functionally, the αKG-dependent hydroxylases are comparable to cytochrome P450 enzymes, which use oxygen and reducing equivalents to oxygenate substrates concomitant with formation of water.[3]

Biological function

αKG-dependent hydroxylases have diverse roles.[4][5] In microorganisms such as bacteria, αKG-dependent dioxygenases are involved in many biosynthetic pathways.[6][7][8] In plants, αKG-dependent dioxygenases are involved in many different reactions in plant metabolism.[9] These include flavonoid biosynthesis,[10] and ethylene biosyntheses.[11] In mammals and humans, αKG-dependent dioxygenase have functional roles in biosyntheses (e.g. collagen biosynthesis[12] and L-carnitine biosynthesis[13]), post-translational modifications (e.g. protein hydroxylation[14]), epigenetic regulations (e.g. histone and DNA demethylation[15]), as well as sensors of energy metabolism.[16]

Many αKG-dependent dioxygenase also catalyse uncoupled turnover, in which oxidative decarboxylation of αKG into succinate and carbon dioxide proceeds in the absence of substrate. The catalytic activity of many αKG-dependent dioxygenases are dependent on reducing agents (especially ascorbate) although the exact roles are not understood.[17][18]

Catalytic mechanism

αKG-dependent dioxygenases catalyse oxidation reactions by incorporating a single oxygen atom from molecular oxygen (O2) into their substrates. This conversion is coupled with the oxidation of the cosubstrate αKG into succinate and carbon dioxide.[1][2] With labeled O2 as substrate, the one label appears in the succinate and one in the hydroxylated substrate:[19][20]

R3CH + O2 + −O2CC(O)CH2CH2CO2− → R3COH + CO2 + −OOCCH2CH2CO2−

The first step involves the binding of αKG and substrate to the active site. αKG coordinates as a bidentate ligand to Fe(II), while the substrate is held by noncovalent forces in close proximity. Subsequently, molecular oxygen binds end-on to Fe cis to the two donors of the αKG. The uncoordinated end of the superoxide ligand attacks the keto carbon, inducing release of CO2 and forming an Fe(IV)-oxo intermediate. This Fe=O center then oxygenates the substrate by an oxygen rebound mechanism.[1][2]

Alternative mechanisms have failed to gain support.[21]

Structure

Protein

All αKG-dependent dioxygenases contain a conserved double-stranded β-helix (DSBH, also known as cupin) fold, which is formed with two β-sheets.[22][23]

Metallocofactor

The active site contains a highly conserved 2-His-1-carboxylate (HXD/E...H) amino acid residue triad motif, in which the catalytically-essential Fe(II) is held by two histidine residues and one aspartic acid/glutamic acid residue. The N2O triad binds to one face of the Fe center, leaving three labile sites available on the octahedron for binding αKG and O2.[1][2] A similar facial Fe-binding motif, but featuring his-his-his array, is found in cysteine dioxygenase.

Substrate and cosubstrate binding

The binding of αKG and substrate has been analyzed by X-ray crystallography, molecular dynamics calculations, and NMR spectroscopy. The binding of the ketoglutarate has been observed using enzyme inhibitors.[24]

Some αKG-dependent dioxygenases bind their substrate through an induced fit mechanism. For example, significant protein structural changes have been observed upon substrate binding for human prolyl hydroxylase isoform 2 (PHD2),[25][26][27] a αKG-dependent dioxygenase that is involved in oxygen sensing,[28] and isopenicillin N synthase (IPNS), a microbial αKG-dependent dioxygenase.[29]

Inhibitors

Given the important biological roles that αKG-dependent dioxygenase play, many αKG-dependent dioxygenase inhibitors were developed. The inhibitors that were regularly used to target αKG-dependent dioxygenase include N-oxalylglycine (NOG), pyridine-2,4-dicarboxylic acid (2,4-PDCA), 5-carboxy-8-hydroxyquinoline, FG-2216 and FG-4592, which were all designed mimic the co-substrate αKG and compete against the binding of αKG at the enzyme active site Fe(II).[30][31] Although they are potent inhibitors of αKG-dependent dioxygenase, they lack selectivity and hence sometimes being referred to as so-called 'broad spectrum' inhibitors.[32] Inhibitors that compete against the substrate were also developed, such as peptidyl-based inhibitors that target human prolyl hydroxylase domain 2 (PHD2)[33] and Mildronate, a drug molecule that is commonly used in Russia and Eastern Europe that target gamma-butyrobetaine dioxygenase.[34][35][36]

Assays

Many assays were developed to study αKG-dependent dioxygenases so that information such as enzyme kinetics, enzyme inhibition and ligand binding can be obtained. Nuclear magnetic resonance (NMR) spectroscopy is widely applied to study αKG-dependent dioxygenases.[37] For example, assays were developed to study ligand binding,[38][39][40] enzyme kinetics,[41] modes of inhibition[42] as well as protein conformational change.[43] Mass spectrometry is also widely applied. It can be used to characterise enzyme kinetics,[44] to guide enzyme inhibitor development,[45] study ligand and metal binding[46] as well as analyse protein conformational change.[47] Assays using spectrophotometry were also used,[48] for example those that measure 2OG oxidation,[49] co-product succinate formation[50] or product formation.[51] Other biophysical techniques including (but not limited to) isothermal titration calorimetry (ITC)[52] and electron paramagnetic resonance (EPR) were also applied.[53] Radioactive assays that uses 14C labelled substrates were also developed and used.[54] Given αKG-dependent dioxygenases require oxygen for their catalytic activity, oxygen consumption assay was also applied.[55]

==Further reading==

  • {{Cite journal|last=Martinez|first=Salette|last2=Hausinger|first2=Robert P.|date=2015-08-21|title=Catalytic Mechanisms of Fe(II)- and 2-Oxoglutarate-dependent Oxygenases|journal=The Journal of Biological Chemistry |volume=290|issue=34|pages=20702–20711|doi=10.1074/jbc.R115.648691|issn=0021-9258|pmc=4543632|pmid=26152721}}
  • {{cite journal |authors= Hegg EL, Que L Jr | title = The 2-His-1-carboxylate facial triad--an emerging structural motif in mononuclear non-heme iron(II) enzymes | journal = Eur. J. Biochem. | volume = 250 | issue = 3 | pages = 625–629 |date=December 1997 | pmid = 9461283 | doi = 10.1111/j.1432-1033.1997.t01-1-00625.x }}.
  • {{cite journal |authors= Myllylä R, Tuderman L, Kivirikko KI | title = Mechanism of the prolyl hydroxylase reaction. 2. Kinetic analysis of the reaction sequence | journal = Eur. J. Biochem. | volume = 80 | issue = 2 | pages = 349–357 |date=November 1977 | pmid = 200425 | doi = 10.1111/j.1432-1033.1977.tb11889.x }}
  • {{cite journal |authors= Valegård K, Terwisscha van Scheltinga AC, Dubus A, Ranghino G, Oster LM, Hajdu J, Andersson I | title = The structural basis of cephalosporin formation in a mononuclear ferrous enzyme | journal = Nat. Struct. Mol. Biol. | volume = 11 | issue = 1 | pages = 95–101 |date=January 2004 | pmid = 14718929 | doi = 10.1038/nsmb712 }}
  • {{cite journal |authors= Price JC, Barr EW, Tirupati B, Bollinger JM Jr, Krebs C | title = The first direct characterization of a high-valent iron intermediate in the reaction of an alpha-ketoglutarate-dependent dioxygenase: a high-spin FeIV complex in taurine/alpha-ketoglutarate dioxygenase (TauD) from Escherichia coli | journal = Biochemistry | volume = 42 | issue = 24 | pages = 7497–7508 |date=June 2003 | pmid = 12809506 | doi = 10.1021/bi030011f }}
  • {{cite journal |authors= Proshlyakov DA, Henshaw TF, Monterosso GR, Ryle MJ, Hausinger RP | title = Direct detection of oxygen intermediates in the non-heme Fe enzyme taurine/alpha-ketoglutarate dioxygenase | journal = J. Am. Chem. Soc. | volume = 126 | issue = 4 | pages = 1022–1023 |date=February 2004 | pmid = 14746461 | doi = 10.1021/ja039113j }}
  • {{cite journal |authors= Hewitson KS, Granatino N, Welford RW, McDonough MA, Schofield CJ | title = Oxidation by 2-oxoglutarate oxygenases: non-haem iron systems in catalysis and signalling | journal = Phil. Trans. R. Soc. A | volume = 363 | issue = 1829 | pages = 807–828 |date=April 2005 | pmid = 15901537 | doi = 10.1098/rsta.2004.1540 }}
  • {{cite journal |authors= Wick CR, Lanig H, Jäger CM, Burzlaff N, Clark T | title = Structural Insight into the Prolyl Hydroxylase PHD2: A Molecular Dynamics and DFT Study | journal = Eur. J. Inorg. Chem. | volume = 31 | issue = 31| pages = 4973–4985 |date=November 2012 | pmid = | doi = 10.1002/ejic.201200391 }}

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2 : Enzymes|Human 2OG oxygenases
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