Holdings: Structure-Based Drug Design on Enzymes of the Fatty Acid Biosynthesis Pathway

Structure-Based Drug Design on Enzymes of the Fatty Acid Biosynthesis Pathway: = Strukturbasiertes Wirkstoffdesign an Enzymen der Fettsäurebiosynthese

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Bibliographic Details
Main Author:	Schiebel, Johannes (Author)
Format:	Thesis Book
Language:	English
Published:	Würzburg 2013
Subjects:	Fettsäurestoffwechsel Kristallstruktur Enoyl-acyl-carrier-protein-Reductase > Enoyl-[acyl-carrier-protein]-Reductase Staphylococcus aureus Inhibition Hochschulschrift
Online Access:	Volltext Inhaltsverzeichnis
Physical Description:	IX, 177, XXXVII Seiten Illustrationen, Diagramme

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adam_text	STRUCTURE-BASED DRUG DESIGN ON ENZYMES OF THE FATTY ACID BIOSYNTHESIS PATHWAY STRUKTURBASIERTES WIRKSTOFFDESIGN AN ENZYMEN DER FETTSAEUREBIOSYNTHESE DOCTORAL THESIS FOR A DOCTORAL DEGREE AT THE GRADUATE SCHOOL OF LIFE SCIENCES, JULIUS-MAXIMILIANS-UNIVERSITAET WUERZBURG, SECTIONS INFECTION AND IMMUNITY / BIOMEDICINE SUBMITTED BY JOHANNES SCHIEDEL FROM NUERNBERG WUERZBURG 2013 TABLE OF CONTENTS TABLE OF CONTENTS.....................................................................................................................................................................I SUMMARY................................................................................................................................................................................... VI ZUSAMMENFASSUNG.............................................................................................................................................................. VIII 1 INTRODUCTION.................................................................................................................................................................. 1 1.1 ANTIBIOTIC RESISTANCE................................................................................................................................................ 1 1.1.1 CLINICALLY RELEVANT CLASSES OF ANTIBACTERIAL DRUGS.................................................................................... 1 1.1.2 RESISTANCE MECHANISMS................................................................................................................................1 1.1.3 METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS (MRSA)...............................................................................2 1.1.4 TUBERCULOSIS................................................................................................................................................... 3 1.2 ANTIBACTERIAL DRUG DISCOVERY................................................................................................................................. 3 1.2.1 HISTORY OF ANTIBACTERIAL DISCOVERY.............................................................................................................. 3 1.2.2 CHALLENGES OF ANTIBACTERIAL DISCOVERY........................................................................................................ 3 1.2.3 NEW CONCEPTS AND STRATEGIES OF ANTIBACTERIAL DRUG DEVELOPMENT......................................................4 1.2.4 IMPORTANCE OF DRUG-TARGET KINETICS........................................................................................................... 5 1.3 BACTERIAL FATTY ACID BIOSYNTHESIS AS A DRUG TARGET............................................................................................ 6 1.3.1 FATTY ACID BIOSYNTHESIS................................................................................................................................. 6 1.3.2 THE ACYL CARRIER PROTEIN..............................................................................................................................8 1.3.3 DIVERSITY IN THE FATTY ACID SYNTHESIS PATHWAY.......................................................................................... 9 1.3.4 ESSENTIALITY OF THE BACTERIAL FATTY ACID BIOSYNTHESIS............................................................................. 10 1.3.5 MYCOLIC ACID SYNTHESIS IN MYCOBACTERIA................................................................................................. 10 1.4 TARGETING KEY STEPS O F THE FAS-II PATHWAY......................................................................................................... 11 1.4.1 THE ENOYL-ACP REDUCTASE FAB! OF 5. AUREUS AND OTHER BACTERIA.......................................................... 11 1.4.2 FABL INHIBITION.............................................................................................................................................. 13 1.4.3 M. TUBERCULOSIS KASA...................................................................................................................................16 1.4.4 INHIBITION OF THE FAS-II CONDENSING ENZYMES..........................................................................................17 1.5 RESEARCH OBJECTIVE................................................................................................................................................. 18 1.5.1 GENERAL QUESTIONS CONCERNING THE FAS-II PATHWAY .............................................................................. 18 1.5.2 QUESTIONS CONCERNING SAFABL, KASA AND THEIR NATURAL SUBSTRATES......................................................18 1.5.3 QUESTIONS CONCERNING THE INHIBITION OF SAFABL AND KASA .................................................................... 19 2 STAPHYLOCOCCUS AUREUS FABL: INHIBITION, SUBSTRATE RECOGNITION, AND POTENTIAL IMPLICATIONS FOR IN VIVO ESSENTIALITY..............................................................................................................................................................................20 2.1 SUMMARY....................................................................................................................... 22 2.2 HIGHLIGHTS.................................................................................................................................................................22 2.3 INTRODUCTION............................................................................................................................................................ 22 2.4 RESULTS......................................................................................................................................................................24 2.4.1 OVERALL STRUCTURE.........................................................................................................................................24 2.4.2 SAFABL INHIBITION..........................................................................................................................................25 2.4.3 INDUCED FIT LIGAND BINDING........................................................................................................................ 26 2.4.4 DIMER - TETRAMER TRANSITION......................................................................................................................28 2.4.5 COOPERATIVITY............................................................................................................................................... 29 2.4.6 COFACTOR SPECIFICITY..................................................................................................................................... 30 2.4.7 BRANCHED-CHAIN SUBSTRATE SPECIFICITY..................................................................................................... 32 2.5 DISCUSSION...............................................................................................................................................................32 2.6 EXPERIMENTAL PROCEDURES..................................................................................................................................... 34 2.6.1 CLONING, EXPRESSION AND PURIFICATION ......................................... . ............................................................34 2.6.2 SITE-DIRECTED MUTAGENESIS, EXPRESSION AND PURIFICATION OF SAFABL MUTANTS.......................................34 2.6.3 CRYSTALLIZATION, DATA COLLECTION AND STRUCTURE DETERMINATION.............................................................34 2.6.4 ANALYTICAL SIZE EXCLUSION CHROMATOGRAPHY............................................................................................. 35 2.6.5 SYNTHESIS OF TRANS-2-ENOYL-COA SUBSTRATES............................................................................................ 35 2.6.6 STEADY-STATE KINETIC ASSAYS....................................................................................................................... 35 2.6.7 INHIBITION KINETICS........................................................................................................................................35 2.7 ACCESSION NUMBERS............................................................................................................................................... 36 2.8 ACKNOWLEDGEMENTS................................................................................................................................................36 2.9 SUPPLEMENTAL INFORMATION................................................................................................................................... 36 2.9.1 SUPPLEMENTAL DATA............................................................................................................................. 36 2.9.2 SUPPLEMENTAL RESULTS................................................................................................................................. 42 2.9.2.1 INHIBITION KINETICS..............................................................................................................................42 2.9.2.2 REDUCTION OF STRAIGHT-CHAIN SUBSTRATES BY SAFABL.........................................................................42 2.9.2.3 SUBSTRATE SPECIFICITY OF SAFABL........................................................................................................ 42 2.9.3 SUPPLEMENTAL DISCUSSION................................................................................................................... 43 2.9.3.1 GLUTAMATE SENSITIVITY........................................................................................................................ 43 2.9.4 SUPPLEMENTAL EXPERIMENTAL PROCEDURES.................................................................................................43 2.9.4.1 CLONING............................................................................................................................................... 43 2.9.4.2 EXPRESSION AND PURIFICATION............................................................................................................. 44 2.9.4.3 CRYSTALLIZATION, DATA COLLECTION AND STRUCTURE DETERMINATION....................................................44 2.9.4.4 STEADY-STATE KINETIC ASSAYS............................................................................................................. 45 2.9.4.5 INHIBITION KINETICS.............................................................................................................................. 46 3 RATIONAL OPTIMIZATION OF DRUG-TARGET RESIDENCE TIME: INSIGHTS FROM INHIBITOR BINDING TO THE STAPHYLOCOCCUS AUREUS FABL ENZYME-PRODUCT COMPLEX................................................................................................48 3.1 KEYWORDS................................................................................................................................................................. 50 3.2 ABSTRACT................................................................................................................................................................... 50 3.3 INTRODUCTION............................................................................................................................................................50 3.4 EXPERIMENTAL PROCEDURES......................................................................................................................................51 3.5 RESULTS......................................................................................................................................................................54 3.6 DISCUSSION............................................................................................................................................................... 64 3.7 ASSOCIATED CONTENT.............................................................................................. 66 3.8 AUTHOR INFORMATION................................................................................................................................................66 3.9 ACKNOWLEDGMENTS..................................................................................................................................................67 3.10 ABBREVIATIONS.................................................................................................................................................... 67 3.11 SUPPORTING INFORMATION..................................................................................................................... 68 4 MOLECULAR BASIS FOR THE NARROW-SPECTRUM ACTIVITY OF THE CLINICAL CANDIDATE CG400549 AND THE RATIONAL DESIGN OF A POTENT BROAD-SPECTRUM PYRIDONE-BASED FABL INHIBITOR...........................................................................74 4.1 KEYWORDS................................................................................................................................................................. 76 4.2 CAPSULE.....................................................................................................................................................................76 4.3 SUMMARY........................................................................... 76 4.4 INTRODUCTION................................................................ 76 4.5 EXPERIMENTAL PROCEDURES...................................................................................................................................... 78 4.5.1 COMPOUND SYNTHESIS ............................... ................................................................................................. 78 4.5.2 EXPRESSION AND PURIFICATION....................................................................................................................... 78 4.5.3 CRYSTALLIZATION...............................................................................................................................................78 4.5.4 DATA COLLECTION AND STRUCTURE DETERMINATION...................................................................................... 79 4.5.5 INHIBITION KINETICS........................................................................... 80 4.5.6 THERMAL SHIFT ASSAY ........................................ . ..........................................................................................81 4.5.7 DOCKING STUDIES........................................................................................................................................... 81 4.5.8 DETERMINATION OF MIC VALUES....................................................................................................................81 4.5.9 IN VIVO PHARMACOKINETICS............................................................................................................................81 4.5.10 IN VIVO EFFICACY........................................................................................................................................ 82 4.6 RESULTS............................... 82 4.7 DISCUSSION................................................................................................................................................................ 96 4.8 ACKNOWLEDGEMENTS................................................................................................................................................99 4.9 FOOTNOTES.............................................................................................................................................................. 100 4.10 SUPPLEMENTARY INFORMATION ................ 101 4.10.1 SUPPLEMENTAL TABLES...........................................................................................................................101 4.10.2 SUPPLEMENTAL FIGURES..........................................................................................................................104 5 PROTONS AND HYDRIDES - WHEREFROM AND WHERETO: FROM A CHEMICAL BINDING POCKET ANALYSIS TO A BIOLOGICAL SUBSTRATE RECOGNITION PROCESS...................................................................................................................... 105 5.1 ABSTRACT..................................................................................................................................................................107 5.2 INTRODUCTION.......................................................................................................................................................... 107 5.3 RESULTS AND DISCUSSION........................................................................................................................................110 5.3.1 ANALYSIS OF THE SAFABL BINDING POCKET CHARACTERISTICS......................................................................... 110 5.3.2 PUTATIVE SUBSTRATE BINDING MODES......................................................................................................... 113 5.3.3 HYDRIDE TRANSFER AND PROTON DELIVERY....................................................................................................114 5.3.4 PROTEIN FLUCTUATIONS RELEVANT FOR SUBSTRATE RECOGNITION ................................................................... 118 5.3.5 LOCATION AND BINDING PROCESS OF ACP-SUBSTRATES.................................................................................119 5.3.6 CONCLUDING REMARKS ............ . ....................................................................................................................121 5.4 METHODS ............. . ................................................................................................................................................ 121 5.4.1 CRYSTALLIZATION, DATA COLLECTION AND STRUCTURE DETERMINATION .......................................................... 121 5.4.2 SITE-DIRECTED MUTAGENESIS, EXPRESSION AND PURIFICATION OF SAFABL VARIANTS ................................... 122 5.4.3 STEADY-STATE KINETICS.................................................................................................................................122 5.4.4 INHIBITION KINETICS...................................................................................................................................... 122 5.4.5 THERMAL SHIFT ASSAY...................................................................................................................................122 5.4.6 CIRCULAR DICHROISM..................................................................................................................................... 122 5.4.7 MOLECULAR DYNAMICS SIMULATIONS........................................................................................................... 123 5.4.8 COMPUTATIONAL DOCKING............................................................................................................................ 124 5.5 ASSOCIATED CONTENT..............................................................................................................................................124 5.5.1 SUPPORTING INFORMATION............................................................................................................................ 124 5.6 AUTHOR INFORMATION..............................................................................................................................................124 5.6.1 CORRESPONDING AUTHOR.............................................................................................................................. 124 5.6.2 NOTES........................................................................................................................................................... 124 5.7 ACKNOWLEDGMENTS................................................................................................................................................ 124 5.8 SUPPLEMENTARY INFORMATION............................................................................................................................... 125 5.8.1 SUPPLEMENTAL TABLES.................................................................................................................................125 5.8.2 SUPPLEMENTAL FIGURES............................................................................................................................... 129 5.8.3 SUPPLEMENTAL MOVIES............................................................................................................................... 135 5.8.4 SUPPLEMENTAL RESULTS AND DISCUSSION................................................................. 136 5.8.4.1 INHIBITION OF SAFABL......................................................................................................................... 136 5.8.4.2 MOLECULAR DYNAMICS SIMULATIONS.................................................................................................. 136 5.8.4.3 COFACTOR BINDING PROCESS............................................................................................................... 137 5.8.4.4 SUBSTRATE RECOGNITION.....................................................................................................................138 6 ACYL CHANNEL OPENING REVEALS HOW THE CONDENSING ENZYME KASA FROM MYCOBACTERIUM TUBERCULOSIS RECOGNIZES MYCOLIC ACID PRECURSORS................................................................................................................ 139 6.1 KEYWORDS............................................................................................................................................................... 141 6.2 CAPSULE.................................................................................................................................................................. 141 6.3 SUMMARY............................................................................................................................................................... 141 6.4 INTRODUCTION.................................................................................................................................................... 141 6.5 EXPERIMENTAL PROCEDURES................................................................................................................................... 143 6.5.1 EXPRESSION AND PURIFICATION................................................................................................................... 143 6.5.2 CRYSTALLIZATION AND DATA COLLECTION...................................................................................................... 143 6.5.3 STRUCTURE DETERMINATION......................................................................................................................... 144 6.5.4 LIPIDOMICS.............................................................................................................................................. . 144 6.5.5 SYNTHESIS OF 3-SUBSTITUTED TLM-DERIVATIVES ...................................................................................... 144 6.5.6 INHIBITION KINETICS........................................ . ...........................................................................................144 6.6 RESULTS..................................................................................................................................................................145 6.6.1 KASA INHIBITION BY 3-SUBSTITUTED TLM-DERIVATIVES ............................................................. 145 6.6.2 IDENTIFICATION OF A PHOSPHOLIPID BOUND TO KASA...................................................................................147 6.6.3 LOCATION OF THE KASA SUBSTRATE BINDING SITES....................................................................................... 148 6.6.4 STRUCTURAL EXPLANATION FOR THE KASA SUBSTRATE PREFERENCES ...... .........................................................150 6.6.5 ACYL-CHANNEL OPENING MECHANISM........................................................................................................151 6.7 DISCUSSION.............................................................................................................................................................154 6.8 ACKNOWLEDGEMENTS............................................................................................................................................. 157 6.9 FOOTNOTES..............................................................................................................................................................158 6.10 SUPPLEMENTARY INFORMATION..........................................................................................................................159 6.10.1 SUPPLEMENTAL TABLES........................................................................................................................... 159 6.10.2 SUPPLEMENTAL FIGURES...........................................................................................................................163 6.10.3 SUPPLEMENTAL MOVIES...........................................................................................................................165 6.10.4 SUPPLEMENTAL EXPERIMENTAL PROCEDURES........................................................ 166 6.10.4.1 LIPIDOMICS.......................................................................................................................................... 166 7 DISCUSSION.................................... . ................................................................................................................... . ....... 167 7.1 S. AUREUS FABL....................................................................................................................................................... 167 7.1.1 SUBSTRATE, COFACTOR AND INHIBITOR RECOGNITION.....................................................................................167 7.1.2 MOLECULAR DETERMINANTS OF AFFINITY AND SELECTIVITY ................................. 169 7.1.3 RATIONAL RESIDENCE TIME OPTIMIZATION - A CASE STUDY WITH SAFABL ....................................... 171 7.1.4 NEW CONCEPTS FOR INHIBITOR DESIGN........................................................................................................172 7.2 M. TUBERCULOSIS KASA........................................................................................................................................... 173 7.2.1 SUBSTRATE AND INHIBITOR RECOGNITION......................................................................................................173 7.2.2 NEW CONCEPTS FOR INHIBITOR DESIGN........................................................................................................174 7.3 INTERACTION BETWEEN ACP AND FAS-II ENZYMES................................................................................................175 8 REFERENCES..................................................................................................................................................................... I 9 APPENDIX.....................................................................................................................................................................XIX 9.1 ABBREVIATIONS......................................................................................................................................................... XIX 9.2 SUPPLEMENTARY MATERIALS AND METHODS.........................................................................................................XXIII 9.2.1 EXPRESSION AND PURIFICATION OF CROTONYL-SAACP....................................................................................XXIII 9.2.2 EXPRESSION AND PURIFICATION OF ACETOACETYL-ACPM.............................................................................. XXVI 9.3 DNA AND PROTEIN SEQUENCES..............................................................................................................................XXIX 9.3.1 SAFABL ...................................... .................................................................................................................XXIX 9.3.2 SAACP . .......................... XXX 9.3.3 ECFABL.........................................................................................................................................................XXXI 9.3.4 KASA.............. ..... ....................................................................................................................................... XXXI 9.3.5 A CPM .........................................................................................................................................................XXXII 10 ACKNOWLEDGEMENTS............................................................................................................................................. XXXIII 11 CURRICULUM VITAE...................................................................................................................................................XXXIV 12 LIST OF PUBLICATIONS............................................................................................................................................... XXXVI 13 AFFIDAVIT................................................................................................................................................................ XXXVII 14 EIDESSTATTLICHE ERKLAERUNG.................................................................................................................................. XXXVII
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genre	(DE-588)4113937-9 Hochschulschrift gnd-content
genre_facet	Hochschulschrift
id	DE-604.BV043530687
illustrated	Illustrated
indexdate	2024-07-10T07:28:07Z
institution	BVB
language	English
oai_aleph_id	oai:aleph.bib-bvb.de:BVB01-028946393
oclc_num	957725009
open_access_boolean	1
owner	DE-384 DE-473 DE-BY-UBG DE-703 DE-1051 DE-824 DE-29 DE-12 DE-91 DE-BY-TUM DE-19 DE-BY-UBM DE-1049 DE-92 DE-739 DE-898 DE-BY-UBR DE-355 DE-BY-UBR DE-706 DE-20 DE-1102
owner_facet	DE-384 DE-473 DE-BY-UBG DE-703 DE-1051 DE-824 DE-29 DE-12 DE-91 DE-BY-TUM DE-19 DE-BY-UBM DE-1049 DE-92 DE-739 DE-898 DE-BY-UBR DE-355 DE-BY-UBR DE-706 DE-20 DE-1102
physical	IX, 177, XXXVII Seiten Illustrationen, Diagramme
psigel	ebook
publishDate	2013
publishDateSearch	2013
publishDateSort	2013
record_format	marc
spelling	Schiebel, Johannes Verfasser (DE-588)1098346610 aut Structure-Based Drug Design on Enzymes of the Fatty Acid Biosynthesis Pathway = Strukturbasiertes Wirkstoffdesign an Enzymen der Fettsäurebiosynthese submitted by Johannes Schiebel Strukturbasiertes Wirkstoffdesign an Enzymen der Fettsäurebiosynthese Würzburg 2013 IX, 177, XXXVII Seiten Illustrationen, Diagramme txt rdacontent n rdamedia nc rdacarrier Dissertation Julius-Maximilians-Universität Würzburg 2013 Zusammenfassung in deutscher und englischer Sprache Fettsäurestoffwechsel (DE-588)4154234-4 gnd rswk-swf Kristallstruktur (DE-588)4136176-3 gnd rswk-swf Enoyl-acyl-carrier-protein-Reductase Enoyl-[acyl-carrier-protein]-Reductase (DE-588)4481400-8 gnd rswk-swf Staphylococcus aureus (DE-588)4182912-8 gnd rswk-swf Inhibition (DE-588)4273127-6 gnd rswk-swf (DE-588)4113937-9 Hochschulschrift gnd-content Staphylococcus aureus (DE-588)4182912-8 s Enoyl-acyl-carrier-protein-Reductase Enoyl-[acyl-carrier-protein]-Reductase (DE-588)4481400-8 s Kristallstruktur (DE-588)4136176-3 s DE-604 Fettsäurestoffwechsel (DE-588)4154234-4 s Inhibition (DE-588)4273127-6 s Erscheint auch als Online-Ausgabe urn:nbn:de:bvb:20-opus-69239 https://nbn-resolving.org/urn:nbn:de:bvb:20-opus-69239 Resolving-System kostenfrei Volltext DNB Datenaustausch application/pdf http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=028946393&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA Inhaltsverzeichnis
spellingShingle	Schiebel, Johannes Structure-Based Drug Design on Enzymes of the Fatty Acid Biosynthesis Pathway = Strukturbasiertes Wirkstoffdesign an Enzymen der Fettsäurebiosynthese Fettsäurestoffwechsel (DE-588)4154234-4 gnd Kristallstruktur (DE-588)4136176-3 gnd Enoyl-acyl-carrier-protein-Reductase Enoyl-[acyl-carrier-protein]-Reductase (DE-588)4481400-8 gnd Staphylococcus aureus (DE-588)4182912-8 gnd Inhibition (DE-588)4273127-6 gnd
subject_GND	(DE-588)4154234-4 (DE-588)4136176-3 (DE-588)4481400-8 (DE-588)4182912-8 (DE-588)4273127-6 (DE-588)4113937-9
title	Structure-Based Drug Design on Enzymes of the Fatty Acid Biosynthesis Pathway = Strukturbasiertes Wirkstoffdesign an Enzymen der Fettsäurebiosynthese
title_alt	Strukturbasiertes Wirkstoffdesign an Enzymen der Fettsäurebiosynthese
title_auth	Structure-Based Drug Design on Enzymes of the Fatty Acid Biosynthesis Pathway = Strukturbasiertes Wirkstoffdesign an Enzymen der Fettsäurebiosynthese
title_exact_search	Structure-Based Drug Design on Enzymes of the Fatty Acid Biosynthesis Pathway = Strukturbasiertes Wirkstoffdesign an Enzymen der Fettsäurebiosynthese
title_full	Structure-Based Drug Design on Enzymes of the Fatty Acid Biosynthesis Pathway = Strukturbasiertes Wirkstoffdesign an Enzymen der Fettsäurebiosynthese submitted by Johannes Schiebel
title_fullStr	Structure-Based Drug Design on Enzymes of the Fatty Acid Biosynthesis Pathway = Strukturbasiertes Wirkstoffdesign an Enzymen der Fettsäurebiosynthese submitted by Johannes Schiebel
title_full_unstemmed	Structure-Based Drug Design on Enzymes of the Fatty Acid Biosynthesis Pathway = Strukturbasiertes Wirkstoffdesign an Enzymen der Fettsäurebiosynthese submitted by Johannes Schiebel
title_short	Structure-Based Drug Design on Enzymes of the Fatty Acid Biosynthesis Pathway
title_sort	structure based drug design on enzymes of the fatty acid biosynthesis pathway strukturbasiertes wirkstoffdesign an enzymen der fettsaurebiosynthese
title_sub	= Strukturbasiertes Wirkstoffdesign an Enzymen der Fettsäurebiosynthese
topic	Fettsäurestoffwechsel (DE-588)4154234-4 gnd Kristallstruktur (DE-588)4136176-3 gnd Enoyl-acyl-carrier-protein-Reductase Enoyl-[acyl-carrier-protein]-Reductase (DE-588)4481400-8 gnd Staphylococcus aureus (DE-588)4182912-8 gnd Inhibition (DE-588)4273127-6 gnd
topic_facet	Fettsäurestoffwechsel Kristallstruktur Enoyl-acyl-carrier-protein-Reductase Enoyl-[acyl-carrier-protein]-Reductase Staphylococcus aureus Inhibition Hochschulschrift
url	https://nbn-resolving.org/urn:nbn:de:bvb:20-opus-69239 http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=028946393&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA
work_keys_str_mv	AT schiebeljohannes structurebaseddrugdesignonenzymesofthefattyacidbiosynthesispathwaystrukturbasierteswirkstoffdesignanenzymenderfettsaurebiosynthese AT schiebeljohannes strukturbasierteswirkstoffdesignanenzymenderfettsaurebiosynthese

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