Biochemstiry - cellular

• Checkpoints control transition between phases of cell cycle
• Regulated by: cyclins, CDKs, and tumor suppressors
• Mitosis (shortest phase): prophase-metaphase-anaphase-telophase
• G₁ and G₀ are of variable duration
• *G = Gap or Growth
• *S = Synthesis

• CDKs: Cyclin-dependent kinases
• -Constitutive and inactive

• Cyclins: Regulatory proteins that control cell cycle events
• -phase specific
• -activate CDKs

Cyclin-CDK complexes: Must be both activated and inactivated for cell cycle to progress

• Tumor suppressors:
• -p53 and hypophophorylated Rb normally inhibit G₁-to-S progression
• -mutations in these genes result in unrestrained cell division

• Permanent: Remain in G₀, regenerate from stem cells
• -Neurons
• -Skeletal and cardiac muscle
• -RBCs

• Stable (quiescent): Enter G₁ from G₀ when stimulated
• -Hepatocytes
• -Lymphocytes

• Labile: Never go to G₀, divide rapidly with short G₁
• -Bone marrow
• -Gut epithelium
• -Skin
• -Hair follicles
• -Germ cells

• Site of synthesis of secretory (exported) proteins and of N-linked oligosaccharide addition to many proteins
• Nissle bodies (RER in neurons): synthesize enzymes (e.g., ChAT [choline acetyltransferase] makes ACh) and peptide neurotransmitters
• Free ribosomes: unattached to any membrane; site of synthesis of cytosolic and organellar proteins
• **Mucus-secreting goblet cells of the small intestine
• **Antibody-secreting plama cells are rich in RER

• Site of ssteroid synthesis and detoxification of drugs and poisons
• **Liver hepatocytes and steroid hormone-producing cells of the adrenal cortex are rich in SER

• Golgi is the distribution center for proteins and lipids from the ER to the vesicles and plasma membrane
• Modifies N-oligosaccharides on asparagine
• Adds O-oligosaccharides on serine and threonine
• Adds mannose-6-phosphate to proteins for trafficking to lysosomes

Endosomes are sorting centers for material from outside the cell or from the Golgi, sending it to lysosomes for destruction or back to the membrane/Golgi for further use

• Inclusion cell disease (I-cell disease):
• -inherited lysosomal storage disorder
• -failure of addition of mannose-6-phosphate to lysosome proteins → enzymes are secreted outside the cell instead of being targeted to the lysosome

• Findings:
• -coarse facial features
• -clouded corneas
• -restricted joint movements
• -high plasma levels of lysosomal enzymes
• -often fatal in childhood

• COPI:
• -Golgi → Golgi (retrograde)
• -Golgi → ER

• COPII:
• -Golgi → Golgi (anterograde)
• -ER → Golgi

• Clathrin:
• -trans-Golgi → lysosomes
• -plasma membrane → endosomes (receptor-mediated endocytosis)

Membrane-enclosed organelle involved in catabolism of very long fatty acids and amino acids

Barrel-shaped protein complex that degrades damaged or unnecessary proteins tagged for destruction with ubiquitin

• Cylindrical structure composed of a helical array of polymerized dimers of α- and β-tubulin
• Each dimer has 2 GTP bound
• Incorporated into flagella, cilia, mitotic spindles
• Grows slowly, collapses quickly
• Also involved in slow axoplasmic transport in neurons

• Molecular motor proteins: transport cellular cargo toward opposite ends of microtubule tracks
• -Dynein = retrograde to microtubule (+ → -)

-Kinesin = anterograde to microtubule (- → +)

• Mebendazole/thiabendazole: antihelminthic
• Griseofulvin: antifungal
• Vincristine/vinblastine: anti-cancer
• Paclitaxel: anti-breast cancer
• Colchicine: anti-gout

• Mutation in the lysosomal trafficking regulator gene (LYST):
• LYST product is required for microtubule-dependent sorting of endosomal proteins into late multivesicular endosomes
• Presentation: recurrent pyogenic infections, partial albinism, and peripheral neuropathy

• 9 + 2 arangement of microtubules
• Axonemal dynein: ATPase that links peripheral 9 doublets and causes bending of cilium by differential sliding of doublets

• Immotile cilia due to a dynein arm defect
• Results in male infertility and decreased female fertility
• Bronchiectasis
• Recurrent sinusitis
• Associated with situs inversus

• Actin and myosin: microvilli, muscle contraction, cytokinesis, adherens junctions
• Microtubule: Movement. Cilia, flagella, mitotic spinddle, axonal trafficking, centriolees
• Intermediate filaments: Structure. Vimentin, desmin, cytokeratin, lamins, glial fibrillary acid proteins (GFAP), neurofilaments

• Asymmetric lipid bilayer
• Contains cholesterol, phospholipids, sphingolipids, glycolipids, and proteins

• Vimentin: connective tissue
• Desmin: muscle
• Cytokeratin: Epithelial cells
• GFAP: NeuroGlia
• Neurofilaments: Neurons

• Na⁺-K⁺ ATPase is located in the plasma membrane with ATP site on cytosolic side
• Each ATP: 3Na⁺ go out; 2K⁺ come in
• During the cycle, the pump is phosphorylated

• Ouabain: inhibits by binding to K+ site
• Cardiac glycosides (digoxin, digitoxin): directly inhibit the Na⁺-K⁺ ATPase, which leads to indirect inhibition of Na⁺/Ca²⁺ exchange → ↑ [Ca²⁺]_i, → ↑ cardiac contractility

• Most abundant protein in the human body
• Extensively modified by posttranslational modification
• Organizes and strengthens ECM

• Type I: most common (90%) - Bone, Skin, Tendon, dentin fascia, cornea, late wound repair
• ----Defective in osteogenesis imperfecta
• Type II: Cartilage (including hyaline), vitreous body, nucleus pulposus
• **Type II: cartwolage
• Type III: Reticulin - skin, blood vessels, uterus, fetal tissue, granulation tissue
• ----Defective in Ehlers-Danlos **Type III: ThreE D)
• Type IV: Basement membrane or basal laminal
• **Type IV: under the floor (basement membrane)
• ----Defective in Alport syndrome
• **Be (So Totally) Cool, Read Books

• 1. Synthesis (RER): Translation of collagen α chains (preprocollagen) − usually Gly-X-Y (X and Y are proline or lysine)
• 2. Hydroxylation (ER): Hydroxylation of specific proline and lysine residues (requires Vitamin C; deficiency → scurvy)
• 3. Glycosylation (ER): Glycosylation of pro-α-chain hydroxylysine residues and formation of procollagen via hydrogen and disulfide bonds (triple helix of 3 collagen α chains). Problems forming the triple helix → osteogenesis imperfecta)
• 4. Exocytosis: exocytosis of procollagen into extracellular space

• 5. Proteolytic processing: Cleavage of disulfide-rich terminal regions of procollagen, transforming it into insoluble tropocollagen
• 6. Crosslinking: Reinforcement of many staggered tropocollagen molecules by covalent lysin-hydroxylysine cross-linkage (by Cu²⁺-containing lysyl oxidase) to make collagen fibrils
• -Problems with cross-linking → Ehlers-Danlos

• Collagen synthesis and structure
• inside and outside fibroblasts

• Genetic bone disorder (brittle bone disease) caused by a variety of gene defects
• Most common form is autosomal dominant with abnormal type I collagen
• Presentation:
• -Multiple fractures with minimal trauma; may occur during the birth process
• -Blue sclera due to the translucency of the connective tissue over the choroidal veins
• 
• -Hearing loss (abnormal middle ear bones)
• -Dental imperfections due to lack of dentin
• Incidence: 1:10,000

• Faulty collagen synthesis causing hyperextensible skin, tendency to bleed (easy bruising), and hypermobile joints
• 6 types
• Inheritance and severity vary; can be autosomal dominant or recessive
• May be associated with joint dislocation, berry aneurysms, organ rupture
• Type I or Type IV collagen  most frequently affected in severe classic Ehlers-Danlos syndrome

• Abnormal type IV collagen; due to a variety of gene defects 
• Most common is X-linked recessive
• Presentation: progressive hereditary nephritis and deafness
• May be associated with ocular disturbances
• *Type IV collagen is important structural component of the basement membrane of the kidney, ears, and eyes

• Stretchy protein within skin, lungs, large arteries, elastic ligaments, vocal cords, ligamenta flava (connect vertebrae → relaxed and stretched conformations)
• Rich in proline and glycine, nonhydroxylated forms
• Tropoelastin with fibrillin scaffolding
• Cross-linkind takes place extracellularly and gives elastin its elastic  properties
• Broken down by elastase, which is normally inhibited by α₁-antitrypsin

• Marfan's syndrome: caused by a defect in fibrillin
• Emphysema: can be caused by α1-antitrypsin deficiency, resulting in excess elastase activity
• wrinkles of aging are due to reduced collagen and elastin production