2-Oxoglutarate-Dependent Oxygenases

506 Pages·2015·15.03 MB·English

by  Robert Hausinger

2-Oxoglutarate-Dependent Oxygenases
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RSC Metallobiology Series
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c.or 3: 2-Oxoglutarate-Dependent Oxygenases
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2-Oxoglutarate-Dependent
Oxygenases
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9/ Department of Microbiology, Michigan State University, USA
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sc. RSC Metallobiology Series No. 3
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9- Preface
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0.1 In the 1960s scientists discovered three examples of 2-oxoglutarate (2OG)-
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oi: dependent oxygenases catalysing the hydroxylation of (i) prolyl residues
g | d in collagen precursors, (ii) the free base thymine and (iii) γ-butyrobetaine.
or During the intervening 50 years or so, a remarkably broad diversity of alter-
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s.rs nate reactions and substrates has been revealed for the 2OG-dependent oxy-
ub genases and extensive advances have been achieved in our understanding
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p:// of their structures and catalytic mechanisms. These mononuclear Fe(ii)
htt enzymes most often catalyse hydroxylation reactions, but other types of
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o chemistries are known including dealkylation, desaturation, cyclization and
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01 halogenation reactions. These reactions are employed in a variety of biolog-
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46. pril ical roles including the biosynthesis of cellular components, the generation
1:A of important small molecules including widely used antibiotics, the disposal
10:2n 23 of undesired molecules, and in regulatory processes such as hypoxic signal-
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d ling. 2OG-dependent oxygenases are also important agrochemical targets
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sh and are being pursued as therapeutic targets for a wide range of diseases
ubli including cancer and anaemia. Given the numerous recent advances and
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biomedicinal interest in this field, we recognized the utility of compiling a
series of in-depth reviews of these enzymes in a single text. Our hope is that
such a timely compendium will be a valuable resource and serve to unite and
stimulate the field.
This book offers an overview of the rapidly evolving field of research involv-
ing 2OG-dependent oxygenases. We begin with four broad summary chapters
that highlight critical aspects of this field. Chapter 1 (Hausinger) explores
the vast enzymatic landscape associated with the amazingly diverse set of
reactions catalysed by 2OG-dependent oxygenases. An overview of the con-
served structural platform and metallocentres employed by 2OG-dependent
oxygenases is presented in Chapter 2 (Schofield and colleagues). Advances
RSC Metallobiology Series No. 3
2-Oxoglutarate-Dependent Oxygenases
Edited by Robert P. Hausinger and Christopher J. Schofield
© The Royal Society of Chemistry 2015
Published by the Royal Society of Chemistry, www.rsc.org
v
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vi Preface
in our mechanistic understanding of these enzymes, including information
on the key intermediates, are highlighted in Chapter 3 (Bollinger, Krebs and
coworkers). Biomimetic analogues that have been helpful in dissecting the
mechanism and metallocentre properties, and which may ultimately enable
the discovery of novel catalysts, are described in Chapter 4 (Que and col-
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0 leagues). These overview discussions set the stage for an additional 17 chap-
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F ters focused on carefully targeted topics.
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5 The substrates for many 2OG-dependent oxygenases are macromolecules,
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2 including proteins, lipids and oligonucleotides. Hydroxylases acting on pro-
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8 lyl and lysyl residues in pro-collagen are presented in Chapter 5 (Myllyharju).
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8 Chapter 6 (Schofield and coworkers) describes work on other protein hydrox-
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9/ ylases that play a central role in hypoxic signalling in animals. The very
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10 rapidly developing field, from both biochemical and physiological perspec-
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1 tives, of 2OG-dependent oxygenases (the JmjC enzymes) that remove methyl
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d groups from lysyl-derived side chains via oxidative dealkylations is described
org | in Chapter 7 (Cheng and Trievel). Chapter 8 (Müller and Hausinger) summa-
sc. rizes knowledge of the DNA/RNA repair enzyme AlkB that catalyses the deal-
bs.r kylation of modified bases and its ALKBH mammalian homologues. Related
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htt demethylases, FTO and ALKBH5, in Chapter 9 (Zheng and He) and ALKBH8
on and its role in synthesis of a modified tRNA in Chapter 10 (Falnes and Ho).
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1 The series of ten-eleven translocase (TET) oxygenases that oxidize 5-meth-
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0:223 conversion of the thymine base within DNA into the novel base J (β-D-gluco-
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o pyranosyloxymethyluracil) by one of these enzymes in selected protozoa is
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he detailed in Chapter 12 (Sabatini and colleagues).
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bli A multitude of other 2OG-dependent enzymes utilize small molecule sub-
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strates and function in diverse roles that include lipid metabolism or syn-
thesis of plant signalling molecules and antibiotics. Chapter 13 (Vaz and van
Vlies) details two enzymes involved in the biosynthesis of carnitine, which
plays a central role in fatty acid metabolism in animals. The metabolism of
the chlorophyll metabolite phytanic acid by a 2OG-dependent hydroxylase
is described in Chapter 14 (Wanders and colleagues). The roles of selected
enzymes during the biosynthesis of flavonoids and gibberellins are sum-
marized in Chapter 15 (Martens and Matern) and Chapter 16 (Hedden and
Phillips), respectively. Chapter 17 (Andersson and Valegård) and Chapter 18
(Smith and Khare) cover roles of 2OG-dependent oxygenases in the biosyn-
thesis of the medicinally important cephalosporin antibiotics and various
halogenated molecules, respectively.
Several enzymes are structurally and mechanistically related to the 2OG-
dependent oxygenases, but do not utilize 2OG as a cosubstrate. Chapter 19
(Rutledge) summarizes the amazing chemistry of isopenicillin N synthase,
which catalyses a unique bicyclization reaction. Formation of the agricultur-
ally important plant signalling molecule ethylene is catalysed by 1-amino-
cyclopropane-1-carboxylate oxidase as described in Chapter 20 (Simaan and
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Preface vii
Réglier). Finally, two enzymes that produce distinct products from an alter-
native 2-oxo acid, 4-hydroxyphenylpyruvate, and their commercial impor-
tance, are detailed in Chapter 21 (Shah and Moran).
We sincerely thank all of the authors for their outstanding contributions,
which reveal the current states of understanding in this ever-expanding field
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8 basic science into medicinal and agricultural benefits. Finally, we feel that
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39/ Chapter 1 Biochemical Diversity of 2-Oxoglutarate-Dependent
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htt     1.2.2  Protein Substrates with Oxygen-Sensing  
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1:A     1.2.5 Histone Demethylases  8
0:223     1.2.6 Other Protein Demethylases  8
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Substrates  9
    1.3.2  Other Oxidative Modifications of  
DNA or RNA  11
1.4  Lipid-Related Metabolism Involving 2OG-Dependent  
Oxygenases  13
1.5  Plant Metabolite Biosynthesis Using 2OG-Dependent  
Oxygenases  15
    1.5.1  2OG-Dependent Oxygenases in Flavonoid  
Biosynthesis  15
    1.5.2  2OG-Dependent Oxygenases of Gibberellin  
Biosynthesis  17
RSC Metallobiology Series No. 3
2-Oxoglutarate-Dependent Oxygenases
Edited by Robert P. Hausinger and Christopher J. Schofield
© The Royal Society of Chemistry 2015
Published by the Royal Society of Chemistry, www.rsc.org
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x Contents
    1.5.3  2OG-Dependent Oxygenases in Alkaloid  
Synthesis  17
    1.5.4  Other Plant-Specific 2OG-Dependent  
Oxygenases  19
1.6  2OG-Dependent Oxygenases Catalysing Reactions  
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org | Metabolism  29
sc. 1.7  2OG-Dependent Oxygenases Involved in Antibiotic 
bs.r  Biosynthesis  29
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htt     1.7.2 Synthesis of Terpenoid Antibiotics  32
on     1.7.3  2OG-Dependent Oxygenases Acting on  
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1:48. April     1.7.4 P Oetphteird Re oSlyenst fhoers 2isO G-Dependent Oxygenases   32
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    1.8.3  4-Hydroxyphenylpyruvate Dioxygenase and 
Hydroxymandelate Synthase  39
Note added in proof   40
Acknowledgements   40
References   40
Chapter 2 Introduction to Structural Studies on 2-Oxoglutarate-
Dependent Oxygenases and Related Enzymes 59
Wei Shen Aik, Rasheduzzaman Chowdhury, Ian J. Clifton,
Richard J. Hopkinson, Thomas Leissing, Michael A. McDonough,
Radosław Nowak, Christopher J. Schofield, and
Louise J. Walport
2.1  Introduction to Structural Studies on  
2-Oxoglutarate- Dependent Oxygenases  59
    2.1.1 Background  59
    2.1.2  2OG Oxygenases Have a Double-Stranded  
β-Helix Core Fold  63
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Contents xi
2.2  Iron Binding Sites in 2OG Oxygenases and  
Related Enzymes  69
2.3 2OG Binding by 2OG Oxygenases  73
2.4 Substrate Binding by 2OG Oxygenases  76
2.5  Structural Aspects of Inhibition of  
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8 The Hydroxylation Paradigm and Beyond 95
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doi: 3.1 Introduction  95
g | 3.2 Mechanism of the Fe/2OG Hydroxylases  96
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n High-Spin Fe(iv) Complex  98
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0:223 [Fe(iv)–Oxo] Species  99
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3.3 Fe/2OG Aliphatic Halogenases  101
    3.3.1  Evidence for H•-Abstracting Haloferryl  
Complexes in the Halogenases  102
    3.3.2  Analysis of Substrate Triggering in the  
Halogenases  103
    3.3.3  Clues as to How SyrB2 Directs Halogenation  
in Preference to Hydroxylation  104
    3.3.4  Evidence that Substrate Positioning  
Ensures Halogenation Rather than  
Hydroxylation  104
3.4  The Epimerization Catalysed by Carbapenem  
Synthase  106
    3.4.1  The Carbapenem Biosynthesis Gene  
Cluster  107
    3.4.2  The Mechanism of Fe/2OG-Mediated  
Stereoinversion  107
    3.4.3 Identity of the Hydrogen Atom Donor  109