Site-selective chemical modification of endogenous proteins:
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| Format: | Thesis Book |
| Language: | English |
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2012
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| Subjects: | |
| Online Access: | Inhaltsverzeichnis |
| Physical Description: | XVIII, 334 S. graph. Darst. |
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| adam_text | IMAGE 1
TABLE OF CONTENTS
TABLE OF CONTENTS V
AMINO ACID SYMBOLS XI
ABBREVIATIONS XIII
CHAPTER 1: INTRODUCTION 1
1.1 SITE-SPECIFIC PROTEIN LABELING: BIOLOGY-BASED APPROACHES 4
1.1.1 SITE-DIRECTED MUTAGENESIS 5
1.1.1.1 SINGLE CYSTEINE MUTATION FOR SITE-SPECIFIC MODIFICATION 5
1.1.1.2 EXPRESSED TETRACYSTEINE MOTIF FOR SELECTIVE LABELING BY ARSENIC
FLUORESCEIN 7
1.1.1.3 EXPRESSED TETRASERINE MOTIF FOR SELECTIVE LABELING 8
1.1.2 NON-CANONICAL AMINO ACID MUTAGENESIS 8
1.1.2.1 RESIDUE-SPECIFIC NCAA INCORPORATION 9
1.1.2.2 SITE-SPECIFIC NCAA INCORPORATION 10
1.1.3 (BIO)ORTHOGONAL REACTIONS FOR TARGETING NON-NATURAL PROTEINS
CARRYING REACTIVE
HANDLES 12
1.1.3.1 REACTIONS ON AZIDO GROUP 12
1.1.3.2 REACTIONS ON ACETYLENE/LODO/KETONE/ALDEHYDE GROUPS 13
1.1.3.3 REACTIONS ON QUADRICYCLANE TAG 14
1.3.3.4 REACTIONS ON PYRROLINE-CARBOXY-LYSINE (PEL) RESIDUE 15
1.1.4 CHEMOENZYMATIC APPROACH 16
1.1.4.1 MODIFICATIONS VIA FUSION WITH SELF-LABELING ENZYME TAGS 16
1.1.4.2 CHEMOENZYMATIC POST-TRANSLATIONAL MODIFICATION 17
1.1.4.3 CHEMOENZYMATIC CO-TRANSLATIONAL MODIFICATION 18
1 . 2 SITE-SPECIFIC ENDOGENOUS PROTEIN MODIFICATION: CHEMISTRY
APPROACHES 1 9
1.2.1 RESIDUE-SPECIFIC MODIFICATIONS 20
1.2.1.1 LYSINE-SPECIFIC MODIFICATIONS 20
1.2.1.2. TYROSINE-SPECIFIC MODIFICATIONS 21
1.2.1.3. MODIFICATION REACTIONS ON ARGININE, HISTIDINE AND
GLUTAMIC/ASPARTIC ACIDS 22
1.2.1.4 ORGANOMETALLIC CATALYSIS-BASED COVALENT MODIFICATIONS 23
1.2.2 SITE-SPECIFIC MODIFICATION ON CYSTEINE/DEHYDROALANINE (DHA) 24
1.2.3 SITE-SPECIFIC MODIFICATION O F ACCESSIBLE DISULFIDE BONDS 26
1.2.4 N-TERMINAL MODIFICATIONS 27
1.2.4.1 N-TERMINAL TRANSAMINATION-BASED MODIFICATIONS 27
1.2.4.2 N-TERMINAL CYSTEINE MODIFICATIONS 28
NATIVE CHEMICAL LIGATION (NCL) . . 28
COUPLING WITH 3-CYANOBENZOTHIOAZOLE (CBT) DERIVATIVE 29
THIAZOLINE-FORMATION . 29
1.2.4.3 N-TERMINAL SERINE/THREONINE MODIFICATIONS 30
1.2.4.4 N-TERMINAL TRYPTOPHAN MODIFICATION 30
HTTP://D-NB.INFO/1026699762
IMAGE 2
1.2.4.5 PK A-BASED N-TERMINAL A-AMINO GROUP MODIFICATION 31
1.2.5 LIGAND-DIRECTED SITE-SPECIFIC MODIFICATION 31
1.2.6 SITE-SPECIFIC PROTEIN MODIFICATION VIA TOTAL CHEMICAL PROTEIN
SYNTHESIS 34
1 . 3 STAUDINGER-TYPE REACTIONS 3 5
1.3.1 STAUDINGER REACTION 35
1.3.2 STAUDINGER LIGATION 37
1.3.3 TRACELESS STAUDINGER LIGATION 39
1.3.3.1 THE FIRST TRACELESS STAUDINGER LIGATION EXAMPLES 40
1.3.3.2 THE FIRST BIOORTHOGONAL TRACELESS STAUDINGER LIGATION 40
1.3.3.3 MECHANISMS OF TRACELESS STAUDINGER LIGATION 41
1.3.3.4 PROTECTION OF PHOSPHINE THIOESTER AS A MORE STABLE BORANE ADDUCT
42
1.3.4. STAUDINGER-PHOSPHITE REACTION 43
1.3.5 SELECTED APPLICATIONS O F STAUDINGER-TYPE LIGATIONS AND OUTLOOK 44
1.3.5.1 FRET-BASED FLUOROGENIC IMAGING: DISPOSAL OF THE ALKOXYL LEAVING
GROUP IN STAUDINGER
LIGATION 44
1.3.5.2 PEPTIDE AND PROTEIN SYNTHESIS: TRACELESS FORMATION OF A NATIVE
AMIDE BOND AFTER
TRACELESS STAUDINGER LIGATION 45
1.3.5.3 PHOSPHORYLATION OF PROTEINS: FORMATION OF A PHOSPHORAMIDATE
LINKAGE AFTER
.STAUDINGER-PHOSPHITE REACTION 46
1 . 4 SYNTHESIS OF FUNCTIONALIZED RHODAMINE DYES 4 8
1.4.1 RHODAMINE FAMILY: AN INTRODUCTION 48
1.4.2 SYNTHESIS O F FUNCTIONALIZED RHODAMINE DYES 51
1.4.2.1 GENERAL 51
1.4.2.2 MODIFICATION AT THE AMINO GROUP: SYNTHESIS OF RH 110 MALEIMIDE
52
1.4.2.3 MODIFICATION AT THE CARBOXYPHENYL RING: SYNTHESIS OF RH 110 NHS
ESTER 52
1.4.2.4 MODIFICATION AT THE CARBOXYL GROUP 53
VIA TERTIARY AMIDE BOUND FORMATION 53
VIA ESTER BOUND FORMATION 54
1.4.3 CHALLENGES 55
1 . 5 REFERENCES 5 5
AIMS AND MOTIVATIONS 75
CHAPTER 2: SITE-SELECTIVE LYSINE MODIFICATION OF ENDOGENOUS PROTEINS
VIA KINETIC PROTEIN LABELING 79
2.1 BIOLOGICAL RELEVANCE OF R N A S E A , H E W L , MYOGLOBIN AND
SOMATOSTATIN 7 9
2.1.1 RNASEA 79
2.1.1.2 THE STRUCTURE OF RNASEA 80
2.1.1.3THE ENZYMATIC FUNCTION OF RNASEA 81
2.1.1.4 RNASEA: A SUITABLE MODEL FOR STUDYING PROTEIN MODIFICATIONS 82
2.1.2 HEN EGG WHITE LYSOZYME (HEWL, LYSOZYME C) 83
2.1.3. HORSE MYOGLOBIN 84
2.1.4 SOMATOSTATIN-14 (SST-14) 85
2 . 2 . HIGHLY SITE-SELECTIVE L A B E I N G O F R N A S E A A T K 1 VIA
K P L 8 6
2.2.1 THE ROLE O F LYSINE RESIDUES 86
IMAGE 3
2.2.2 MONOBIOTINYLATION O F RNASE A UNDER KINETICALLY CONTROLLED
CONDITIONS 87
2.2.3 RECOVERY O F UNMODIFIED RNASE A 91
2.2.4 IDENTIFICATION O F THE MODIFICATION SITE 91
2.2.5 PRESERVATION OF CATALYTIC ACTIVITY AFTER KINETICALLY CONTROLLED
PROTEIN LABELING 93
2 . 3 SITE-SELECTIVE BIOTINYLATION OF H E W L , S S T - 1 4 A N D HORSE
MYOGLOBIN 9 4
2.3.1 HIGHLY SITE-SELECTIVE BIOTINYLATION O F HEWL AT K1 VIA KPL 95
2.3.1.1 MONOBIOTINYLATION OF HEWL UNDER KINETICALLY CONTROLLED LABELING
CONDITIONS 95
2.3.1.2 DEMONSTRATION OF THE SITE-SELECTIVITY AT K1 IN
BIOTIN-LC-(K1)HEWL 96
2.3.1.3 MEASUREMENT OF RETAINED ENZYMATIC ACTIVITY OF BIOTIN-LC-(K1
)HEWL (2-5) VIA LYSOZYME
FUNCTIONAL ASSAY 96
2.3.2 SITE-SELECTIVE LABELING O F THE SST-14 AT K9 VIA KPL 98
2.3.3 MONO-BIOTINYLATION O F HORSE MYOGLOBIN 100
2.3.4 SCHEMATIC SUMMARIZATION O F KINETIC PROTEIN LABELING 102
2 . 4 IDENTIFICATION OF IMPORTANT FACTORS CONTRIBUTING T O THE
SITE-SELECTIVITY 1 0 3
2.4.1 SOLVENT ACCESSIBILITY 104
2.4.2 SOLVENT ACCESSIBILITY MAY PLAY A KEY ROLE IN DETERMINING THE
MODIFICATION SITE OF
RNASE A 104
2.4.3 HYDROGEN BOND INTERACTION MIGHT BE A KEY FACTOR IN DETERMINING THE
MODIFICATION
SITE O F LYSOZYME C 105
2.4.4 ADDITIONAL CONSIDERATIONS 107
2 . 5 DESIGN OF B I O T I N - T E O - P P G - O S U ( 2 - 1 0 ) FOR
MONO-ETHYNYLATION OF R N A S E A 1 0 8
2.5.1 DESIGN O F BIOTIN-TEO-PPG-OSU (2-10) 109
2.5.2 SYNTHESIS O F BIOTIN-TEO-PPG-OSU (2-10) 109
2.5.3 MONO-ETHYNYLATION O F RNASE A USING BIOTIN-TEO-PPG-OSU (2-10) 112
2 . 6 DESIGN OF B I O T I N - T E O - E T H Y N Y L - N H S ( 2 - 2 8 )
FOR SITE-SELECTIVE ETHYNYLATION O F
R N A S E A 1 1 4
2.6.1 DESIGN O F BIOTIN-TEO-ETHYNYL-NHS (2-28) 114
2.6.2 SYNTHESIS O F BIOTIN-TEO-ETHYNYL-NHS (2-28) 115
2.6.3 CONSIDERATIONS FOR THE SYNTHESIS O F BIOTIN-TEO-ETHYNYL-NHS (2-28)
116
2.6.4. NMR INTERPRETATION O F 2-27 117
2.6.5 MONO-ETHYNYLATION O F RNASE A AT K1 119
2.6.6 DEMONSTRATION O F K1 SITE-SELECTIVITY. 121
2.6.7 SITE-SPECIFIC CLICK LABELING O F ETHYNYL-(K1 )RNASE A (2-29) 123
2 . 7 DESIGN OF B I O T I N - T E O - A Z I D O - N H S ( 2 - 3 9 ) FOR
SITE-SELECTIVE A Z I D E INCORPORATION VIA
K P L 1 2 4
2 . 7 . 1 DESIGN O F BIOTIN-TEO-AZIDO-NHS (2-39) 125
2.7.2 SYNTHESIS O F BIOTIN-TEO-AZIDO-NHS (2-39) 127
2.7.3 FULL NMR INTERPRETATION O F BIOTIN-TEO-AZIDO-COOH (2-38) 128
2.7.4 SITE-SELECTIVE AZIDE INCORPORATION INTO RNASE A VIA OPTIMIZED KPL
PROCEDURES
USING BIOTIN-TEO-AZIDO-NHS (2-39) 130
2.7.5 DEMONSTRATION OF THE K1 SITE-SELECTIVITY 133
2.7.6 FICTIONAL ASSAY O F AZIDO-(K1) RNASE A AND THE RECOVERED RNASE A
135
2.7.7 SITE-SPECIFIC STAUDINGER LIGATION ON AZIDO-(K1)RNASE A (2-40) 137
2.7.7A DESIGN AND SYNTHESIS OF RHO-TEO-PHOSPHINE (2-47) 137
IMAGE 4
2.7.7.2 NMR CHARACTERIZATION OF RHO-TEO-PHOSPHINE (2-48) 140
2.7.7.3 STAUDINGER LIGATION ON AZIDO-(K1)RNASE A (2-40) USING
RHO-TEO-PHOSPHINE (2-47). 142
2 . 8 S H O R T SUMMARY 1 4 3
2 . 9 REFERENCES 1 4 6
CHAPTER 3: SYNTHESIS OF BIOTIN-TEO-ETHYNYL-ALLYL-GLY AS A PROMISING
AGENT FOR THE SITE-SELECTIVE TYROSINE MODIFICATION VIA KPL APPROACH 151
3.1 PD-CATALYZED N - A N Y L I C ALKYLATION AS A SUITABLE LABELING
REACTION FOR ADDRESSING
TYROSINE RESIDUES 1 5 1
3 . 2 DESIGN AND SYNTHESIS OF B I O T I N - T E O - E T H Y N Y L - A L
L Y L - G L Y FOR K P L PROTEIN LABELING
1 5 2
3.2.1 DESIGN O F BIOTIN-TEO-ETHYNYL-ALLYL-GLY. 152
3.2.2 SYNTHESIS O F BIOTIN-TEO-ETHYNYL-ALLYL-GLY 153
3.2.3 SYNTHESIS O F N-(4-HYDROXY-2-BUTENYL)-N-PROPARGYLAMINE (3-3) 154
3.2.4 SYNTHESIS O F THE BUILDING BLOCK B (3-6) FROM 3-3 155
3.2.5 DESIGN AND SYNTHESIS O F BIOTIN-TEO-COOH (2-14) 158
3.2.6 SYNTHESIS O F BIOTIN-TEO-ETHYNYL-ALLYL-GLY (3-8) 159
3.2.7 1 H-NMR CHARACTERIZATION O F BIOTIN-TEO-ETHYNYL-ALLYL-GLY (3-8)
160
3 . 3 FUTURE O U T L O O K 1 6 1
3 . 4 S H O R T S U M M A R Y 1 6 4
3 . 5 REFERENCES 1 6 5
CHAPTER 4: LIGAND-INDUCED LENGTH-CONTROLLED (LILC) APPROACH FOR
SITE-SELECTIVE AVIDIN LABELING 167
4.1 H E N E G G W H I T E AVIDIN, A T E T R A M E R I C ( + ) - B I O T
I N BINDING PROTEIN 1 6 7
4 . 2 VISUALIZATION OF THE LYSINE DISTRIBUTION ON AVIDIN 1 6 9
4 . 3 MEASUREMENT OF SURFACE DISTANCES BETWEEN THE BIOTIN AND LYSINES
AROUND THE
BINDING POCKET 1 7 1
4 . 4 DESIGN AND SYNTHESIS OF B I O T I N - B D A - A Z I D O - N H S (
4 - 7 ) AS THE LIGAND-INDUCED A N D
LENGTH-CONTROLLED LABELING REAGENT 1 7 2
4.4.1 DESIGN O F BIOTIN-BDA-AZIDO-NHS (4-7) 172
4.4.2 SYNTHESIS O F BIOTIN-BDA-AZIDO-NHS (4-7) 173
4.4.3 CONSIDERATIONS IN THE SYNTHESIS O F BIOTIN-BDA-AZIDO-NHS (4-7) 174
4.4.4 NMR CHARACTERIZATION 175
4 . 5 SITE-SPECIFIC LABELING OF AVIDIN USING B I O T I N - B D A - A Z I
D O - N H S ( 4 - 7 ) 1 7 6
4.5.1 THE LILC AVIDIN LABELING SCHEME 176
4.5.2 IDENTIFICATION O F THE MODIFICATION SITE 177
4.5.3 ESTIMATION O F THE LABELING YIELD 179
4 . 6 SITE-SPECIFIC LABELING OF A Z I D O - ( K 1 1 1 ) A V I D I N VIA
C L I C K REACTION 1 8 1
4 . 7 S H O R T S U M M A R Y 1 8 2
4 . 8 REFERENCES 1 8 5
CHAPTER 5: CFPP-MEDIATED TRACELESS STAUDINGER LIGATION FOR THE
MODIFICATION OF AZIDO- PROTEINS 187
5.1 COMPARISON OF SEVERAL PHOSPHINE LIGANDS IN MEDIATING TRACELESS
STAUDINGER
IMAGE 5
LIGATION 1 8 8
5.1.1 PHOSPHINOMETHANETHIOL (D) 188
5.1.2 O-PHOSPHINOBENZENETHIOL (E) 189
5.1.3 PHOSPHINOMETHANOL (F) 189
5.1.4 O-PHOSPHINOPHENOL (G) 189
5.1.5 PHOSPHINOIMIDAZOLE (H) 190
5 . 2 RATIONAL DESIGN OF THE PHOSPHINE LIGAND, C F P P 1 9 0
5.2.1 THE SIX CONSIDERATIONS 191
5.2.2 RATIONAL DESIGN O F THE CFPP PHOSPHINE LIGAND 191
5.3 SYNTHESIS OF C F P P , A C - C F P P AND D A N S Y L - C F P P 1 9 5
5.3.1 DESCRIPTION O F THE SYNTHETIC SCHEME 195
5.3.2 SEVERAL KEY CONCERNS IN THE SYNTHESIS 196
5.3.3 NMR CHARACTERIZATIONS 198
5.4.4 STABILITY ASSESSMENT OF AC-CFPP (5-6) VIA 31 P-NMR 199
5 . 5 REACTIVITY PROFILING OF C F P P - A C ( 5 - 6 ) ON THE M O D E L P
E P T I D E - H - A H A - L Y S - T Y R - O H
( 5 - 2 2 ) 2 0 1
5.5.1 DESIGN AND SYNTHESIS O F THE MODEL PEPTIDE-H-AHA-LYS-TYR-OH (5-22)
201
5.5.1.1 DESIGN OF THE MODEL PEPTIDE-H-AHA-LYS-TYR-OH (5-22) 201
5.5.1.2 SYNTHESIS OF THE MODEL PEPTIDE-H-AHA-LYS-TYR-OH (5-22) 202
5.5.1.3 NMR CHARACTERIZATION OF H-AHA-LYS-TYR-OH (5-22) 203
5.5.2MODEI REACTION BETWEEN AC-CFPP (5-6) AND H-AHA-LYS-TYR-OH (5-22)
205
5 . 6 ELUCIDATION OF THE LIGATION MECHANISM VIA ISOTOPE TRACING
EXPERIMENTS 2 0 7
5.6.1 SYNTHESIS O F THE SECOND AZIDO-PEPTIDE (5-32)FOR MECHANISTIC
STUDIES 207
5.6.2 THE PREDOMINATE ACYL-TRANSFER MECHANISM 208
5 . 7 ESTIMATION OF THE REACTION KINETIC CONSTANT K 2 2 1 0
5 . 8 SITE-SPECIFIC LABELING OF A Z I D O - ( K 1 ) R N A S E A ( 2 - 4
0 ) BY D A N S Y L - C F P P ( 5 - 1 0 ) VIA
C F P P - L I G A T I O N 2 1 1
5 . 9 SHORT SUMMARY 2 1 3
5 . 1 0 REFERENCES 2 1 5
CHAPTER 6: EFFICIENT SYNTHESIS OF A FUNCTIONALIZED RHODAMINE B DYE
LIBRARY 217
6.1 T H E RATIONALE OF DERIVATIZATION OF RHODAMINE VIA ESTERIFICATION 2
1 8
6 . 2 DEVELOPMENT OF THE PREPARATION AND PURIFICATION PROCEDURES OF R H
B ESTERS ... 2 1 9
6 . 3 SYNTHESIS OF A R H B E S T E R - B A S E D FUNCTIONAL D Y E
LIBRARY 2 2 1
6 . 4 REPRESENTATIVE INTERPRETATION OF 1 H - N M R A N D 1 3 C - N M R
SPECTRA OF R H B ESTERS VIA
2 D - N M R S 2 2 4
6 . 6 OPTICAL CHARACTERISTICS OF R H B (THIO)ESTER PROBES 2 2 6
6 . 7 S H O R T SUMMARY 2 2 8
6 . 8 REFERENCES 2 2 9
CHAPTER 7: EXPERIMENTAL PROCEDURES 233
7.1 MATERIALS AND REAGENTS 2 3 3
7 . 2 INSTRUMENTATION 2 3 4
7 . 3 METHODS/TECHNOLOGIES 2 3 5
IMAGE 6
7 . 4 PROTEIN MODIFICATIONS 2 4 5
7 . 5 ORGANIC SYNTHESIS 2 5 4
7 . 6 REFERENCES 3 0 7
CHAPTER 8: CONCLUSIONS AND OUTLOOK 309
8.1 CONCLUSIONS 3 0 9
8 . 2 O U T L O O K 3 1 3
8 . 3 A POTENTIAL APPLICATION OF K P L : D U A L KINETIC PROTEIN
LABELING FOR THE
PREPARATION OF A S M A R T ENZYME 3 1 5
8 . 4 REFERENCES 3 1 7
APPENDIX 319
ACKNOWLEDGEMENT 325
LIST OF PUBLICATIONS 329
SELECTED CONFERENCES (ORAL) 330
ERKLARUNG 331
DECLARATION OF ORIGINALITY 333
|
| any_adam_object | 1 |
| author | Chen, Xi 1986- |
| author_GND | (DE-588)1027834469 |
| author_facet | Chen, Xi 1986- |
| author_role | aut |
| author_sort | Chen, Xi 1986- |
| author_variant | x c xc |
| building | Verbundindex |
| bvnumber | BV040543610 |
| ctrlnum | (OCoLC)819524304 (DE-599)BSZ37530391X |
| dewey-full | 547.7 |
| dewey-hundreds | 500 - Natural sciences and mathematics |
| dewey-ones | 547 - Organic chemistry |
| dewey-raw | 547.7 |
| dewey-search | 547.7 |
| dewey-sort | 3547.7 |
| dewey-tens | 540 - Chemistry and allied sciences |
| discipline | Chemie / Pharmazie |
| format | Thesis Book |
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| owner | DE-188 DE-355 DE-BY-UBR DE-29T |
| owner_facet | DE-188 DE-355 DE-BY-UBR DE-29T |
| physical | XVIII, 334 S. graph. Darst. |
| publishDate | 2012 |
| publishDateSearch | 2012 |
| publishDateSort | 2012 |
| record_format | marc |
| spelling | Chen, Xi 1986- Verfasser (DE-588)1027834469 aut Site-selective chemical modification of endogenous proteins vorgelegt von Xi Chen 2012 XVIII, 334 S. graph. Darst. txt rdacontent n rdamedia nc rdacarrier Ulm, Univ., Diss., 2012 Aminosäuren (DE-588)4142205-3 gnd rswk-swf (DE-588)4113937-9 Hochschulschrift gnd-content Aminosäuren (DE-588)4142205-3 s DE-604 DNB Datenaustausch application/pdf http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=025389456&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA Inhaltsverzeichnis |
| spellingShingle | Chen, Xi 1986- Site-selective chemical modification of endogenous proteins Aminosäuren (DE-588)4142205-3 gnd |
| subject_GND | (DE-588)4142205-3 (DE-588)4113937-9 |
| title | Site-selective chemical modification of endogenous proteins |
| title_auth | Site-selective chemical modification of endogenous proteins |
| title_exact_search | Site-selective chemical modification of endogenous proteins |
| title_full | Site-selective chemical modification of endogenous proteins vorgelegt von Xi Chen |
| title_fullStr | Site-selective chemical modification of endogenous proteins vorgelegt von Xi Chen |
| title_full_unstemmed | Site-selective chemical modification of endogenous proteins vorgelegt von Xi Chen |
| title_short | Site-selective chemical modification of endogenous proteins |
| title_sort | site selective chemical modification of endogenous proteins |
| topic | Aminosäuren (DE-588)4142205-3 gnd |
| topic_facet | Aminosäuren Hochschulschrift |
| url | http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=025389456&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA |
| work_keys_str_mv | AT chenxi siteselectivechemicalmodificationofendogenousproteins |