Genetics of Steroid Biosynthesis And Function

BOOK COVER......Page 1
HALF-TITLE......Page 2
TITLE......Page 4
COPYRIGHT......Page 5
CONTENTS......Page 6
PREFACE TO THE SERIES......Page 8
PREFACE......Page 9
2. STEROL BIOSYNTHESIS......Page 14
THE ENZYMES......Page 15
THE ROLE OF COFACTORS AND ACCESSORY PROTEINS......Page 19
CHOLESTEROL TRANSPORT VERSUS STEROID INTERCONVERSION AS THE RATE-LIMITING STEP......Page 21
THE IMPORTANCE OF Km AND RELATIVE SUBSTRATE SPECIFICITY OF COMPETING ENZYMES IN DETERMINING THE END PRODUCTS OF STEROIDOGENESIS......Page 23
CONTROL OF STEROIDOGENESIS BY TISSUE ZONATION......Page 28
LESSONS FROM NATURAL MUTATIONS AND KNOCKOUTS......Page 33
LESSONS FROM PREGNANCY AND PARTURITION......Page 35
REFERENCES......Page 37
INTRODUCTION......Page 50
HMGCoA biosynthesis......Page 52
HMG-Co reductase and mevalonate formation......Page 53
Cyclization of squalene......Page 54
Lanosterol 14a-demethylase (CYP51), a member of the cytochrome P450 superfamily......Page 55
Is sterol -reductase a member of the lamin B receptor/sterol reductase multigene family?......Page 56
Sterol A-isomerase, a member of the sigma receptor family......Page 57
Sterol -reductase, a member of the lamin B receptor/sterol reductase superfamily......Page 58
COORDINATE CONTROL OF BIOSYNTHESIS OF CHOLESTEROL WITH TRANSCRIPTION FACTORS OF THE SREBP FAMILY......Page 59
Smith-Lemli-Opitz syndrome (SLOS)......Page 62
Desmosterolosis......Page 63
REFERENCES......Page 64
THE VITAMIN D BIOSYNTHETIC PATHWAY......Page 70
THE VITAMIN D BIOSYNTHETIC ENZYMES ARE MITOCHONDRIAL FORMS OF CYTOCHROME P450......Page 72
VITAMIN D 25-HYDROXYLASE......Page 73
VITAMIN D 24-HYDROXYLASE......Page 74
VITAMIN D 1-HYDROXYLASE......Page 75
The molecular genetics of 1-hydroxylase deficiency (VDDR-I)......Page 80
Structure-function correlations in P450c1α......Page 84
REFERENCES......Page 87
INTRODUCTION......Page 93
BILE ACID BIOSYNTHESIS PATHWAYS......Page 95
The classical (or neutral) pathway......Page 97
Regulation of bile acid biosynthesis......Page 98
MAJOR REGULATORY ENZYMES IN BILE ACID BIOSYNTHESIS......Page 99
Cholesterol 7-hydroxylase......Page 100
Regulation of cholesterol 7-hydroxylase......Page 101
Regulation of the CYP7A1 gene transcription......Page 103
Molecular mechanisms of regulation......Page 106
Sterol 27-hydroxylase......Page 107
Oxysterol 7-hydroxylase......Page 108
Sterol 12-hydroxylase......Page 109
GENETIC DEFECTS IN BILE ACID BIOSYNTHESIS......Page 110
Defective modification of the steroid nucleus......Page 111
3-C-hydroxysteroid dehydrogenase/isomerase (3-HSD) deficiency (OMIM entry 231100)......Page 112
Defective side-chain oxidation......Page 113
Secondary defects......Page 114
REFERENCES......Page 115
INTRODUCTION......Page 127
STRUCTURE OF THE STEROIDOGENIC CELL......Page 128
DE NOVO CHOLESTEROL SYNTHESIS......Page 131
CHOLESTEROL TRANSPORT INTO STEROIDOGENIC CELLS......Page 132
CHOLESTEROL ESTER HYDROLYSIS: LYSOSOMAL......Page 135
CHOLESTEROL ESTER HYDROLYSIS: EXTRALYSOSOMAL......Page 136
CHOLESTEROL MOVEMENT AFTER LYSOSOMAL HYDROLYSIS......Page 137
CHOLESTEROL TRANSPORT TO THE INNER MITOCHONDRIAL MEMBRANE......Page 138
Structure/function analysis of StAR......Page 142
Post-translational modifications of StAR: phosphorylation......Page 144
Transcriptional regulation......Page 145
CONCLUSIONS......Page 147
REFERENCES......Page 148
BIOCHEMISTRY OF STEROID 21-HYDROXYLASE......Page 158
Oxygen and water binding......Page 160
CYP21 GENE STRUCTURE......Page 161
Naturally occurring transcripts......Page 163
5' Flanking sequences controlling transcription......Page 164
Salt wasting......Page 166
Virilization......Page 167
Mutations causing 21-hydroxylase deficiency......Page 169
Deletions and large gene conversions......Page 170
Nonsense and frameshift mutations......Page 171
Ile-172-Asn (I172N)......Page 172
Arg-356-Trp (R356W)......Page 173
Normal polymorphisms......Page 174
Mutation detection and approaches to prenatal diagnosis......Page 175
Classification of disease seventy......Page 177
Explanations for “discordance” of genotype and phenotype......Page 178
ACKNOWLEDGMENT......Page 179
REFERENCES......Page 180
Zonal location of steroid biosynthesis......Page 192
Catalytic mechanism......Page 193
Characteristics of the human CYP11B genes......Page 194
Regulation of cortisol biosynthesis......Page 196
Angiotensin II......Page 197
Corticotropin (ACTH)......Page 198
Bovine......Page 199
Human......Page 201
Clinical presentation......Page 203
Genetic analysis......Page 205
Clinical presentation......Page 206
Genetic analysis......Page 208
Clinical presentation......Page 209
Genetic analysis......Page 210
Other forms of hyperaldosteronism......Page 211
Allelic variation in CYP11B2......Page 212
Mutation frequencies in CYP11B1 and CYP11B2......Page 213
REFERENCES......Page 214
8. 3-HYDROXYSTEROID DEHYDROGENASE/…......Page 222
Biochemical characteristics......Page 223
Human 3-HSD type I and type II genes and their related pseudogenes......Page 224
Phylogeny of the vertebrate 3-HSD gene family......Page 226
Localization and ontogeny in the human testis......Page 230
Localization and ontogeny in the human ovary......Page 231
Localization and ontogeny in human placenta......Page 232
Localization and ontogeny in the human adrenal gland......Page 233
Clinical features......Page 235
At age of diagnosis......Page 236
At puberty......Page 245
Classical 3-HSD deficiency......Page 246
Non-classical 3-HSD deficiency......Page 247
No mutation in the HSD3B1 gene......Page 248
Advantages of using intact cells to assess enzymatic characteristics......Page 249
Apparent instability of mutant proteins associated with the salt-wasting form of 3-HSD deficiency......Page 253
Genotype-phenotype relationships......Page 255
Structure-function relationships......Page 256
Sequence variants in the HSD3B2 gene versus non-classical 3-HSD deficiency......Page 257
CONCLUSION......Page 258
REFERENCES......Page 259
HISTORY......Page 272
ONE ENZYME OR TWO?......Page 274
MECHANISM OF CATALYSIS......Page 275
MODELING OF HUMAN CYP17......Page 276
REDOX PARTNERS......Page 282
PHYSIOLOGY......Page 284
DELETIONS, PREMATURE TRUNCATIONS, FRAMESHIFTS AND SPLICING ERRORS......Page 287
AMINO ACID SUBSTITUTIONS—COMBINED 17-HYDROXYLASE/17,20-LYASE DEFICIENCY......Page 293
MUTATIONS CAUSING ISOLATED 17,20-LYASE DEFICIENCY......Page 295
SUMMARY......Page 297
REFERENCES......Page 298
INTRODUCTION......Page 305
AROMATASE DEFICIENCY IN HUMANS......Page 307
THE AROMATASE KNOCKOUT (ArKO) MOUSE......Page 309
CONCLUSIONS......Page 311
REFERENCES......Page 312
11. 17-HYDROXYSTEROID DEHYDROGENASE AND 5-REDUCTASE DEFICIENCIES......Page 315
INTRODUCTION......Page 316
Role of androgens in sex differentiation......Page 317
The human 17-HSD/17-KSR gene family......Page 318
Clinical features of 17-HSD/KSR deficiency......Page 328
Biological diagnosis......Page 329
Molecular diagnosis......Page 330
5-REDUCTASE DEFICIENCY......Page 332
Structure and function......Page 333
SRD5A2 polymorphisms and prostate cancer......Page 334
Clinical features of 5-reductase type 2 deficiency......Page 335
Biological diagnosis......Page 337
Molecular diagnosis......Page 338
Management......Page 346
REFERENCES......Page 348
INTRODUCTION......Page 358
11-hydroxysteroid dehydrogenase type 1......Page 359
11-hydroxysteroid dehydrogenase type 2......Page 361
Apparent cortisone reductase deficiency......Page 362
Recombinant mice lacking the HSD11B1 gene......Page 363
Apparent mineralocorticoid excess......Page 364
Mineralocorticoid receptor specificity......Page 365
Genetic basis for AME......Page 366
AME “type ll”......Page 368
HSD11B2 as a candidate gene for hypertension and renal disease......Page 369
17-HYDROXYSTEROID DEHYDROGENASES (17-HSD)......Page 370
REFERENCES......Page 371
INTRODUCTION......Page 379
SR-B1 knockout mouse......Page 381
Cholesterol side-chain cleavage enzyme (CYP11A) deficient rabbit......Page 382
Aromatase knockout mouse......Page 383
Steroidogenic factor 1 (SF-1) knockout mouse......Page 384
SUMMARY AND PERSPECTIVES......Page 385
REFERENCES......Page 386
INTRODUCTION......Page 390
STRUCTURAL FEATURES OF NUCLEAR RECEPTOR FAMILY MEMBERS......Page 392
DIVERSITY OF THE NUCLEAR RECEPTOR FAMILY: EVOLUTIONARY ASPECTS......Page 393
Chaperone binding and NR synthesis......Page 394
DNA binding......Page 396
Ligand binding......Page 401
Coactivators and corepressors......Page 403
Coactivators......Page 404
Cointegrators......Page 406
Corepressors......Page 407
CHROMATIN......Page 408
STABLE COMPLEXES......Page 409
DIVERSITY OF MECHANISMS IMPLICATED IN STUDIES OF COREGULATOR FUNCTION......Page 411
ALTERNATE MECHANISMS OF GENE REGULATION......Page 412
CONCLUSIONS......Page 413
REFERENCES......Page 414
INTRODUCTION......Page 428
STEROIDS GOVERN BRAIN DEVELOPMENT AND FUNCTION......Page 429
CHOLESTEROL SYNTHESIS IN BRAIN......Page 432
Steroids are present in brain......Page 433
Molecular evidence for steroidogenic enzymes in brain......Page 435
Steroidogenesis in brain extracts......Page 436
Are brain steroid levels independent of peripheral synthesis?......Page 438
LOCAL STEROID METABOLISM AND THE MITOCHONDRION......Page 440
STEROID HORMONE NUCLEAR RECEPTORS ARE ABUNDANT IN BRAIN......Page 445
MEMBRANE-ASSOCIATED STEROID RECEPTORS......Page 446
NEUROSTEROID ACTION AT NEUROTRANSMITTER RECEPTORS......Page 447
THE PERIPHERAL BENZODIAZEPINE RECEPTOR; CHOLESTEROL TRANSPORT......Page 448
Emopamil-binding protein......Page 450
Are sterol (and steroid) targets generic sigma sites?......Page 451
STEROL SYNTHESIS AND METABOLISM IS CRUCIAL TO BRAIN FUNCTION......Page 452
Oxysterol metabolism in brain......Page 454
How might sterols modulate neuronal activity?......Page 455
Cholesterol metabolism and cell death......Page 456
Steroids and cell death......Page 457
Intracellular targets for apoptosis induction......Page 458
Receptors for apoptotic oxysterols......Page 459
OXYSTEROLS AND NEUROSTEROIDS: IS THERE A LINK WITH AGEING?......Page 463
A CONFUSING DIVERSITY OF NUCLEAR RECEPTORS: THE RIFAMPICIN EXAMPLE......Page 465
DEVELOPMENT, STEROL SIGNALING AND SUBCELLULAR TARGETING......Page 466
CONCLUSIONS AND OBSERVATIONS......Page 468
REFERENCES......Page 470
INDEX......Page 499