Molecular Biology Inteiijgence Unit

Tetrapyrroles Birth, Life and Death

Martin J. Warren, PhD Protein Science Group Department of Biosciences University of Kent Canterbury, Kent, UK

Alison G. Smith, PhD Department of Plant Sciences University of Cambridge Cambridge, UK

Landes Bioscience Springer Science+Business Media Austin, Texas New York, New York USA USA CONTENTS^

Preface xv

1. An Historical Introduction to and Synthesis 1 Michael R. Moore Historical Introduction to and Porphyrias 1 Structure 4 The Early Chemical Era 9 The Biochemical Descriptive Era 10 Early Description of Porphyria 11 Classification of Porphyrias 12 Enzymes 14 Acute Porphyria 15 Nonacute Porphyrias 17 Porphyria in Animals 18 Porphyrin Synthesis in the Animal Kingdom 19 The Harderian Gland 19 Phototherapy and Cancer 19 Retrospective Diagnoses 20 Ephemera: Porphyrinurias 21

2. Biosynthesis of 5-Aminolevulinic Acid 29 DieterJahn and Dirk W. Heinz Condensation of Succinyl-CoA and Glycine into Aminolevulinic Acid 29 Transfer RNA-Dependent Aminolevulinic Acid Formation 30

3. 5-Aminolaevulinic Acid Dehydratase, Porphobilinogen Deaminase and III Synthase 43 Heidi L. Schubert, Peter T. Erskine andJonathan B. Cooper 5-Aminolaevulinic Acid Dehydratase 43 Porphobilinogen Deaminase 58 Uroporphyrinogen III Synthase 61

4. Transformation of Uroporphyrinogen III into Protohaem 74 Johanna E. Cornah and Alison G Smith Uroporphyrinogen III Decarboxylase 76 Coproporphyrinogen III Oxidase/Dehydrogenase 77 Protoporphyrinogen IX Oxidase 79 Ferrochelatase 81 Organization of Pathway 82

5. Inherited Disorders of Haem Synthesis: The Human Porphyrias 89 Michael N. Badminton and George H. Elder Overview 89 Molecular Genetics and Pathogenesis 93 Mechanisms of Disease 96 New Approaches to Management 97 6. Degradation: Mechanistic and Physiological Implications 101 Angela Wilks Evolution and Biological Function of Heme Oxygenase 101 Sequence and Structural Conservation within the Heme Oxygenase Enzymes 103 Crystallographic Studies 103 Mechanism of Heme Oxygenase 107 Reduction to 110 Biliverdin IXa Reductase 110 Biliverdin Dtp1 Reductase 113

7. Regulation of Mammalian Heme Biosynthesis 116 Amy E. Medlock and Harry A. Dailey Regulation of Heme Biosynthesis by ALA Synthase 117 Regulation at Sites Other Than ALAS 121

8. in Photodynamic Therapy 128 David I. Vernon and Ian Walker Brief History 128 Singlet Oxygen: The Cytotoxic Agent 129 Singlet Oxygen Targets 129 Light Delivery and Requirement 130 Photodynamic Damage 130 Mechanisms ofTumour and Cellular Uptake 131 Tetrapyrroles in Photodynamic Therapy 131 Haematoporphyrin Derivative (HpD) and Photofrin 131 The Ideal Properties of a Photosensitiser 132 Second Generation Photosensitisers 133 5,10,15,20 Tetrakis (meso-hydroxyphenyl) (m-THPC, Foscan, temoporfin) 133 5,10,15,20 Tetrakis (meso-hydroxyphenyl) Bacteriochlorin (m-THPBC) 134 Benzoporphyrin Derivative (BPD, Verteporfin) 135 Tin Ethyl Etiopurpurin (SnEt2, Purlytin, Rostaporfin) 136 Mono-L-Aspartyl Chlorin e6 (Npe6, MACE, Talaporfin) 136 Palladium-Bacteriopheophorbide (TOOKAD, WST009) 137 2- [ 1 -hexyloxyethyl] -2-Devinyl Pyropheophorbide-a (HPPH, Photochlor) 138 Phthalocyanines 139 Lutetium Texaphyrin (Lu-tex, Motexafin Lutetium) 139 5-Aminolaevulinic Acid 140 Clinical ALA-PDT 141 Other Applications of ALA-PDT 141 Aminolaevulinic Acid Esters 141 Photodetection of Tumours 142 9. Heme Transport and Incorporation into Proteins 149 Linda Thony-Meyer Localization of Heme in Prokaryotes 150 Bacterial Heme Transport 151 Heme Transport in Eukaryotes 153 Unassisted Heme Transport 155 Heme-Protein Assembly 155

10. Heme and Hemoproteins 160 Andrew W. Munro, Hazel M. Girvan, KirstyJ. McLean, Myles R. Cheesman and David Leys The Heme Synthetic Pathway 160 Structural Variations of the Heme 162 Heme Iron Coordination in Hemoproteins 165 Diversity of Hemoprotein Form and Function 168 Spectroscopic Analysis of Hemoproteins 171 Novel Aspects and Future Prospects 175

11. Novel Heme-Protein Interactions—Some More Radical Than Others 184 Ann Smith

Heme as a Sensor: Interactions of Heme with Proteins That Lead to Recognition of Gaseous Molecules: Oxygen, Carbon Monoxide and Nitric Oxide 186 Heme Binding to Ion Channels 187 Novel Low-Spin Heme-Protein Interactions 188 Heme-Binding Proteins That Are Protective, Preventing Heme-Mediated Oxidative Stress 189 Heme Transport across Enterocytes and Proof of Principle 193 Interactions of Heme with Transcription Factors 195 Heme-Protein Interactions and the Control of Orcadian Rhythms... 196 Novel Heme-Protein Interactions for the Control of Intracellular Heme Levels 199 Relationships between ATP Concentrations, Oxygen Tension and Heme Transporters, Many of Which Also Interact with Porphyrins 201

12. Synthesis and Role of Bilins in Photosynthetic Organisms 208 Nicole Frankenberg-Dinkel andMatthew J. Terry Structure and Spectral Properties of Protein-Bound Bilins 208 Synthesis of Biliverdin IXa by Heme Oxygenases 210 Biosynthesis of Bilins by Ferredoxin-Dependent Reductases 212 Assembly of Phycobiliproteins and 216 The Roles of Bilins in Photosynthetic Organisms 216 13- Phytochromes: Bilin-Linked Photoreceptors in Bacteria and Plants... 221 Matthew J. Terry andAlex C. McCormac The Phytochromes—A Diverse Family of Photoreversible Photoreceptors 222 Photosensory Domains 224 Physiological Roles of Phytochrome-Like Proteins in Prokaryotes 226 Phytochrome Function in Flowering Plants 227 Specific Roles for Specific Phytochromes 227 Phytochrome Mode ofAction 229 Phytochrome Regulation of Synthesis 229

14. Biosynthesis of Chlorophyll and 235 DerrenJ. Heyes and C. Neil Hunter The Insertion of the Central Magnesium Ion 237 Methylation of Ring C 238 The Missing Link in Chlorophyll Biosynthesis: The Formation of the Isocyclic Ring E of 239 Reduction of the 8-Vinyl Group 240 Two Routes for the Reduction of Pchlide 241 POR: A Light-Driven Enzyme 241 DPOR: A Multi-Subunit Enzyme 243 The Steps Unique to Bacteriochlorophyll Biosynthesis 244 The Final Steps: Addition and Reduction of the Phytol Tail 245

15. Regulation of Tetrapyrrole Synthesis in Higher Plants 250 MatthewJ. Terry andAlison G. Smith Regulation of the Plant Tetrapyrrole Pathway—At the Heart of Plant Metabolism? 252 Turning on the Tap)—Regulation of the Synthesis of the Initial Precursor, ALA 253 Decision Time at the Branchpoints 256 Regulation of the Chlorophyll Branch 258

16. Regulation of the Late Steps of Chlorophyll Biosynthesis 263 Woljhart Riidiger Light Regulation via NADPH: Protochlorophyllide Oxidoreductase (POR) 264 Regulation of Biosynthesis 267 A New Role for Carotenoids? 269

17. Chlorophyll Breakdown 274 Bernhard Krautler Chlorophyll Breakdown in Higher Plants 274 Early Steps 275 Cleavage of the Chlorophyll Macroring 276 The Arrival at Colorless and Nonfluorescent Chlorophyll Breakdown Products 278 Breakdown Beyond the Stage of Colorless Tetrapyrrolic Catabolites... 280 Chlorophyll Catabolites from Other Sources 282

18. : Biosynthesis of the Ring 286 Ross M. Graham, Evelyne Deery andMartin J. Warren The First Common Step: Production of Precorrin-2 287 The Aerobic Pathway 288 Production of Hydrogenobyrinic Acid 291 Proteins of Unknown Function 293 The Anaerobic Pathway 293 Production of Cobalt-Precorrin-6A 295

19. Conversion of Cobinamide into Coenzyme B12 300 Jorge C. Escalante-Semerena, Jesse D. Woodson, Nicole R. Buan and Carmen L. Zayas Attachment of 5-Deoxyadenosine, the Upper (Cop) Ligand of Coenzyme B12 300 The Nucleotide Loop Assembly (NLA) Pathway 304

20. The Regulation of 317 Jeffrey G. Lawrence The Complexity of Cobalamin 317 Cobalamin in Context: Regulating a Branch Point 319 Operon Induction and Physiological Significance 321 Operon Repression and mRNA Binding 323 The Synergy of Cobalamin Transport and Synthesis 324

21. Coenzyme BI2-Catalyzed Radical Isomerizations 330 Dominique Padovani andRuma Banerjee Structural Insights into the B,2-Dependent Isomerases 331 Co-C Bond Activation in B12-Dependent Isomerases 333 Radical Flights: Conformational Changes at Play 336 Rearrangement Reactions Catalyzed by B12-Dependent Enzymes 338

22. Biosynthesis of Siroheme and Coenzyme F430 343 Martin J. Warren, Evelyne Deery and Ruth-Sarah Rose Siroheme Biosynthesis 343 Coenzyme F430 Biosynthesis 346

23. Role of Coenzyme F430 in Methanogenesis 352 Evert C. Duin Methanogenesis 353 Free Factor 430 354 Name That Signal 355 EPR Signals in Whole Cells 358 Structure of MCR and the Nickel Site 360 Oxidation State of Nickel in xkc MCRoxl Form 362 Activation and Inactivation of Methyl-Coenzyme M Reductase 363 Prelude to the Catalytic Mechanism 366 Catalytic Mechanism 367 Anaerobic CH4 Oxidation 370

MCR Is Still a Mystery 370

24. The Role of Siroheme in Sulfite and Nitrite Reductases 375 M. Elizabeth Stroupe and Elizabeth D. Getzoff Siroheme-Containing Sulfite and Nitrite Reductases Represent a Single Enzyme Class 375 Diversity between the SiR and NiR Enzymes 377 Symmetry Defines Homology between the Assimilatory and Dissimilatory Enzymes 378 SiRs and NiRs Have Multiple Centers and Intricate Spectroscopic Features 378 X-Ray Crystallographic Structures Support the Spectroscopic Data... 378 Siroheme Is at the Heart of the Six-Electron Reduction of Sulfite

to Sulfide or Nitrite to Ammonia 379

Siroheme Anchors the Transformation of Sulfite to Sulfide

or Nitrite to Ammonia 381 The Siroheme Tetrapyrrole Shows Significant Departure from Planarity 382 Siroheme's Structural and Electronic Characteristics Control Anion Interactions 386

A Possible n Cation Radical Intermediate 387

25. The Role of Heme dl in Denitrification 390 StuartJ. Ferguson Structure of Cytochrome cd\ 391 Mechanism of Nitrite Reduction 394 Insights into dx heme Chemistry from Model Compound Studies 395 Biosynthesis of dx heme 396

Index 401