Genetic diseases of steroid metabolism .pptx

Steroid
This article is about the family of polycyclic chemical compounds. For the drugs, also used as performance-enhancing substances, see Anabolic steroid. For the scientific journal, see Steroids (journal). For the Death Grips EP, see Steroids (Crouching Tiger Hidden Gabber Megamix).
Complex chemical diagram
Structure of 24-ethyl-lanostane, hypothetical a steroid with 32 carbon atoms. Its core ring system (ABCD), composed of 17 carbon atoms, is shown with IUPAC-approved ring lettering and atom numbering.: 1785f 
A steroid is a biologically active organic compound with four rings arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes which alter membrane fluidity; and as signaling molecules. Hundreds of steroids are found in plants, animals and fungi. All steroids are manufactured in cells from the sterols lanosterol (opisthokonts) or cycloartenol (plants). Lanosterol and cycloartenol are derived from the cyclization of the triterpene squalene.

The steroid core structure is typically composed of seventeen carbon atoms, bonded in four "fused" rings: three six-member cyclohexane rings (rings A, B and C in the first illustration) and one five-member cyclopentane ring (the D ring). Steroids vary by the functional groups attached to this four-ring core and by the oxidation state of the rings. Sterols are forms of steroids with a hydroxy group at position three and a skeleton derived from cholestane.: 1785f  Steroids can also be more radically modified, such as by changes to the ring structure, for example, cutting one of the rings. Cutting Ring B produces secosteroids one of which is vitamin D3.

Examples include the lipid cholesterol, the sex hormones estradiol and testosterone,: 10–19  and the anti-inflammatory drug dexamethasone.

Filled-in diagram of a steroid
Space-filling representation
Ball-and-stick diagram of the same steroid
Ball-and-stick representation
5α-dihydroprogesterone (5α-DHP), a steroid. The shape of the four rings of most steroids is illustrated (carbon atoms in black, oxygens in red and hydrogens in grey). The nonpolar "slab" of hydrocarbon in the middle (grey, black) and the polar groups at opposing ends (red) are common features of natural steroids. 5α-DHP is an endogenous steroid hormone and a biosynthetic intermediate.
Nomenclature
Chemical diagram
Gonane, the simplest steroid, consisting only of the common steroid nucleus
Chemical diagram
Steroid 5α and 5β stereoisomers: 1786f 
Gonane, also known as steran or cyclopentanoperhydrophenanthrene, the simplest steroid and the nucleus of all steroids and sterols, is composed of seventeen carbon atoms in carbon-carbon bonds forming four fused rings in a three-dimensional shape. The three cyclohexane rings (A, B, and C in the first illustration) form the skeleton of a perhydro derivative of phenanthrene. The D ring has a cyclopentane structure. When the two methyl groups and eight carbon side ch

1. Genetic Diseases of Steroid Metabolism: From Enzymes to Clinical Manifestations

2. Introduction to Steroid Metabolism Steroid hormones: Essential for normal sexual development, stress response, and fluid/electrolyte balance Three main classes: Sex steroids, glucocorticoids, and mineralocorticoids Synthesis requires precisely controlled expression of biosynthetic enzymes in various tissues Enzyme deficiency can result in disordered hormone synthesis, affecting health Recent advances: cDNA and genomic genes encoding each enzyme have been cloned Focus: Review of genetic studies and clinical manifestations of enzyme deficiencies

3. Key Steroid-Metabolizing Enzymes Cytochromes P450: Mixed-function oxidases Utilize molecular oxygen and NADPH Microsomal and mitochondrial types Examples: 17α-hydroxylase, 21-hydroxylase, aromatase Short-Chain Dehydrogenases: Catalyze reversible reactions Use NAD+ or NADP+ as electron acceptors Examples: 3β-, 11β-, and 17β-hydroxysteroid dehydrogenases

4. Cytochrome P450 Structure and Function Molecular weight: ≈ 50,000 Contains heme (iron chelated to protoporphyrin IX) Membrane-bound in eukaryotes Catalyze oxidative conversions of lipophilic substrates Require accessory electron transport proteins: Microsomal: NADPH-dependent cytochrome P450 reductase Mitochondrial: Adrenodoxin reductase and adrenodoxin

5. Short-Chain Dehydrogenases: Structure and Function Typically 250-300 amino acid residues Found in cytosol or endoplasmic reticulum Catalyze reversible reactions No accessory proteins required Examples of reactions: Conversion of hydroxyl to keto groups Reduction of keto groups to hydroxyls Cofactors: NAD+ or NADP+

6. Pathways of Steroid Biosynthesis: Adrenal Gland Zona Fasciculata: Cortisol synthesis from cholesterol Enzymes involved: CYP11A, 3β-HSD, CYP17, CYP21, CYP11B1 "17-deoxy" pathway: Corticosterone synthesis Zona Glomerulosa: Aldosterone synthesis No 17α-hydroxylase activity Final steps: CYP11B2 (aldosterone synthase) Regulation: Cortisol: Regulated by ACTH via cAMP Aldosterone: Regulated by potassium and angiotensin II via Ca2+ and protein kinase C

7. Pathways of Steroid Biosynthesis: Testis Primary androgen: Testosterone Synthesized in Leydig cells Regulated by luteinizing hormone (LH) via cAMP Key steps: Cholesterol to pregnenolone (CYP11A) Pregnenolone to 17α-hydroxypregnenolone (CYP17) 17α-hydroxypregnenolone to dehydroepiandrosterone (CYP17) Dehydroepiandrosterone to androstenedione (3β-HSD) Androstenedione to testosterone (17β-HSD) Note: Stronger 17,20-lyase activity in testis compared to adrenal cortex

8. Pathways of Steroid Biosynthesis: Ovary Cyclic variations in steroid synthesis Primary follicle: Granulosa cells synthesize estrogens Estradiol secretion exceeds estrone Estrogen synthesis: Testosterone → Estradiol (CYP19/aromatase) Androstenedione → Estrone (CYP19/aromatase) Regulation: Follicle-stimulating hormone (FSH) Corpus luteum: Formed after LH surge Secretes progesterone and estrogen

9. Pathways of Steroid Biosynthesis: Placenta Synthesizes large amounts of progesterone and estrogens Progesterone synthesis: Cholesterol → Pregnenolone (CYP11A) Pregnenolone → Progesterone (placental 3β-HSD) Estrogen synthesis: Dehydroepiandrosterone sulfate (from fetal adrenal) → Dehydroepiandrosterone Dehydroepiandrosterone → Androstenedione (3β-HSD) Androstenedione → Estrone (CYP19/aromatase) Estrone → Estradiol (17β-HSD) Estriol: Produced from 16α-hydroxylated androgen metabolites (fetal liver origin)

10. Cholesterol Desmolase (CYP11A) Function: Converts cholesterol to pregnenolone Three oxidations: 22R and 20R hydroxylations, 20,22 carbon-carbon bond cleavage Requires 3 O2 molecules and 6 electrons Mitochondrial enzyme Gene: CYPLLA on chromosome 15q23-24 Structure: 9 exons over ≈ 20 kb Protein: 482 amino acids (mature form)

11. Congenital Lipoid Adrenal Hyperplasia Caused by cholesterol desmolase deficiency Autosomal recessive inheritance Clinical features: Inability to synthesize all steroids in adrenals and gonads No elevated precursor steroids Large cytoplasmic lipid droplets in adrenal cortex Sodium wasting, hypovolemia, hyperkalemia Males: Female-appearing external genitalia, inguinal testes Females: Normal at birth, sexually infantile Treatment: Glucocorticoid and mineralocorticoid replacement, sex hormone replacement in adolescence

12. 17α-Hydroxylase/17,20-Lyase (CYP17) Functions: 17α-hydroxylation: Pregnenolone → 17α-hydroxypregnenolone 17,20-lyase: 17α-hydroxypregnenolone → Dehydroepiandrosterone Microsomal cytochrome P450 Gene: CYP17 on chromosome 10q24.3 Structure: 8 exons over 6.7 kb Protein: 508 amino acids, 57 kDa

13. 17α-Hydroxylase Deficiency Rare form of congenital adrenal hyperplasia (≈ 1% of cases) Autosomal recessive inheritance Biochemical features: Poor cortisol synthesis Elevated 17-deoxysteroids (e.g., deoxycorticosterone) Clinical features: Hypertension, hypokalemia (mineralocorticoid excess) Sexual development issues: Males: Female-appearing external genitalia Females: Normal at birth, sexually infantile Partial deficiency: Milder phenotypes possible

14. Genetic Basis of 17α-Hydroxylase Deficiency Caused by mutations in CYP17 gene Mutation types: Complete deficiency: Frameshifts, nonsense mutations Partial deficiency: Missense mutations, in-frame deletions Examples of mutations: W17X: Nonsense mutation, no enzyme activity P342T: Missense mutation, 40% residual activity I480 + 4nt: Frameshift mutation, no enzyme activity Genotype-phenotype correlations: >20% activity: Some androgen synthesis >50% activity: Normal male development

15. 3β-Hydroxysteroid Dehydrogenase Deficiency Enzyme: 3β-HSD (HSD3B2 gene on chromosome 1p13) Function: Converts Δ5 to Δ4 steroids (e.g., pregnenolone → progesterone) Clinical features: Salt-wasting in severe cases Varying degrees of undervirilization in males Mild virilization in females Mutations: W171X: Nonsense mutation, no enzyme activity A245P: Missense mutation, unstable enzyme Y253N: Missense mutation, no enzyme activity

16. 21-Hydroxylase Deficiency Most common form of congenital adrenal hyperplasia Enzyme: CYP21 (chromosome 6p21.3) Function: Converts progesterone → deoxycorticosterone, 17-hydroxyprogesterone → 11-deoxycortisol Clinical forms: Salt-wasting: Severe aldosterone deficiency Simple virilizing: Androgen excess without salt-wasting Non-classic: Mild, late-onset symptoms Mutations: Deletions/conversions: Most severe phenotype I172N: Simple virilizing form V281L: Non-classic form

17. 11β-Hydroxylase Deficiency Second most common form of congenital adrenal hyperplasia Enzyme: CYP11B1 (chromosome 8q22) Function: Converts 11-deoxycortisol → cortisol, deoxycorticosterone → corticosterone Clinical features: Androgen excess (virilization) Hypertension (mineralocorticoid excess) Mutations: R448H: Common in Moroccan Jews Q356X: Nonsense mutation R384Q: Missense mutation affecting proton transfer

18. Aldosterone Synthase Deficiency Rare disorder of aldosterone biosynthesis Enzyme: CYP11B2 (chromosome 8q22) Function: Catalyzes final steps of aldosterone synthesis Clinical features: Salt-wasting Failure to thrive Hyponatremia, hyperkalemia Mutations: V386A: Affects 18-oxidase activity R181W: Variable effects on enzyme activity

19. 5α-Reductase Deficiency Disorder of androgen metabolism Enzyme: SRD5A2 (chromosome 2p23) Function: Converts testosterone → dihydrotestosterone Clinical features: Male pseudohermaphroditism Ambiguous genitalia at birth Possible virilization at puberty Mutations: G115D: Alters NADPH binding R227X: Nonsense mutation R246W: Affects enzyme stability

20. Summary and Future Directions Steroid metabolism disorders: Complex interplay of enzymes and clinical manifestations Advances in molecular genetics have elucidated many causative mutations Genotype-phenotype correlations emerging for some disorders Future research directions: Identifying novel mutations and their functional consequences Developing targeted therapies based on molecular defects Improving prenatal diagnosis and genetic counseling Investigating potential gene therapies for severe enzyme deficiencies Importance of interdisciplinary approach: Endocrinology, genetics, and molecular biology