Carbonyl reductases and pluripotent hydroxysteroid dehydrogenases of the short-chain dehydrogenase, reductase superfamily [Elektronische Ressource] : structural aspects of oligomerization in 3α-hydroxysteroid dehydrogenase, carbonyl reductase from Comamonas testosteroni ; new approaches for efficient protein design / vorgelegt von Frank Hoffmann

Fh

Sujets

• Biologie

Informations

• Publié par: philipps-universitat_marburg
• Publié le: 01 janvier 2009
• Nombre de lectures: 38
• Poids de l'ouvrage: 10 Mo

Extrait

Carbonyl Reductases and Pluripotent Hydroxysteroid
Dehydrogenases of the Short-Chain Dehydrogenase/Reductase
Superfamily:
Structural Aspects of Oligomerization in 3 -Hydroxysteroid
Dehydrogenase /Carbonyl Reductase from Comamonas testosteroni:
New Approaches for efficient Protein Design



Dissertation
zur
Erlangung des Doktorgrades
der Naturwissenschaften
(Dr. rer. nat.)


dem
Fachbereich Biologie
der
PHILIPPS-UNIVERSITÄT MARBURG


vorgelegt von
Frank Hoffmann
aus Siegen

Marburg/Lahn 2009
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vom Fachbereich Biologie der Philipps‐Universität Marburg  
als Dissertation angenommen                                                                 17. Juni 2009 
 
Erstgutachter:                                                                                            Prof. Dr. W. Buckel 
Zweitgutachter:                          Prof. Dr. E. Maser 
Tag der mündlichen Prüfung:                                                                 17. Juli 2009 






Meiner Familie in Liebe gewidmet





















Part I


Carbonyl Reductases and Pluripotent Hydroxysteroid Dehydrogenases of
the Short-Chain Dehydrogenase/Reductase Superfamily
Page 2 ff




Part II

Structural Aspects of Oligomerisation in 3 α-Hydroxysteroid Dehydro-
genase /Carbonyl Reductase from Comamonas testosteroni:
New Approaches for efficient Protein Design
Page 69 ff












Part I


Carbonyl Reductases and Pluripotent Hydroxysteroid Dehydrogenases of
the Short-Chain Dehydrogenase/Reductase Superfamily


Frank Hoffmann


Institute of Toxicology and Pharmacology for Natural Scientists,
University Medical School Schleswig-Holstein, Campus Kiel,
Brunswiker Strasse 10, 24105 Kiel, Germany



Published in:
Drug Metabolism Reviews
Volume 39, Issue 1 January 2007
Pages 87 – 144







Table of Contents 3

Part I
Table of Contents
Abstract ................................................................................................................ 5
I Introduction ............................................................................................... 6
I.1 Carbonyl Reduction................................................................................................. 6
I.2 Enzymes Mediating Carbonyl Reduction................................................................ 7
1.1 The Aldo-Keto Reductase (AKR) Superfamily.................................................. 9
1.2 Short-Chain Dehydrogenase/Reductase (SDR) Superfamily ........................... 10
I.3 Hydroxysteroid Dehydrogenases as Carbonyl Reductases.................................... 11
II General Features of the SDR Superfamily Enzymes........................... 13
II.1 Historical Background: Functional Characterization ............................................ 13
II.2 SDR Superfamily Classification............................................................................ 14
II.3 Structural Features of the SDR Members.............................................................. 16
II.3.1 Catalytic Triade and Catalytic Mechanism ...................................................... 18
II.3.2 Substrate Binding and Substrate-Binding Loop ............................................... 21
II.3.3 Cofactor Binding.............................................................................................. 22
II.3.4 C-terminal Extension and 3 -Helices 23 10
II.3.5 Oligomerization and Interfaces........................................................................ 23
III Pluripotent Carbonyl Reductases of the SDR Superfamily................ 27
III.1 Carbonyl Reductases in Non-Mammals ................................................................ 29
III.1.1 3/20 β-Hydroxysteroid Dehydrogenase of Streptomyces hydrogenans.......... 29
III.1.2 3-Hydroxysteroid Dehydrogenase/Carbonyl Reductase of Comamonas
testosteroni........................................................................................................ 30
III.1.3 Insect Carbonyl Reductase: Sniffer of Drosophila melanogaster .................... 31
III.2 Carbonyl Reductases in Mammals ........................................................................ 32
III.2.1 Monomeric Cytosolic NADPH-Dependent Carbonyl Reductases................... 32
III.2.1.1 Human Carbonyl Reductase 1 (CBR1) ............................................... 32
III.2.1.2 9-Keto-Prostaglandin Reductase and 15-Hydroxy-Prostaglandin
Dehydrogenase.................................................................................... 36
III.2.1.3 Human Carbonyl Reductase 3 (CBR3) and 4 (CBR4) ........................ 37 Table of Contents 4

III.2.1.4 Chinese Hamster Carbonyl Reductases (CHCR 1-3).......................... 38
III.2.1.5 Rat Carbonyl Reductases (iCR, nCR, rtCR)........................................ 39
III.2.1.6 Pig Testicular Carbonyl Reductase (PTCR) ....................................... 40
III.2.1.7 Tetrameric Peroxisomal Carbonyl Reductase .................................... 41
III.2.1.8 Tetrameric Mitochondrial Carbonyl Reductases................................ 41
III.2.1.9 Dimeric Microsomal Carbonyl Reductase: 11 -HSD Type 1............. 43
IV Biological Functions of Carbonyl-Reducing Enzymes ........................ 48
IV.1 Roles in Steroid and Prostaglandin Metabolism.................................................... 48
IV.2 Tetrahydrobiopterin Synthesis............................................................................... 49
IV.3 Neuroprotection by Carbonyl Reductase? ............................................................. 51
IV.4 Quinone Detoxification.......................................................................................... 54
IV.5 Carbonyl Reduction in Drug Metabolism and Pharmacology............................... 56
IV.6 Role in Chemotherapy Resistance ......................................................................... 58
IV.7 Protection against Tobacco Smoke-Derived Lung Cancer.................................... 61
IV.8 Detoxification of Insecticides ................................................................................ 65
V Physiological Implications......................................................................66
VI Perspectives.............................................................................................. 67
Zusammenfassung............................................................................................. 68
VI References ..............................................................................................161
VII Figure/Table List:.................................................................................. 210




Abstract 5

I Abstract
Carbonyl reduction of aldehydes, ketones and quinones to their corresponding hydroxy de-
rivatives plays an important role in the phase-I metabolism of many endogenous (biogenic
aldehydes, steroids, prostaglandins, reactive lipid peroxidation products) and xenobiotic
(pharmacologic drugs, carcinogens, toxicants) compounds. Carbonyl-reducing enzymes are
grouped into two large protein superfamilies, the aldo-keto reductases (AKR) and the short-
chain dehydrogenases/reductase