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Flashcards in Biochemistry - Cellular Deck (22):
1

Cell cycle phases

  • Regulation
  • Phases

  • Regulation
    • Checkpoints control transitions between phases of cell cycle.
    • This process is regulated by cyclins, cyclin-dependent kinases (CDKs), and tumor suppressors.
  • Phases
    • G1 and G0 are of variable duration.
      • G = Gap or Growth.
    • S = Synthesis.
    • Mitosis (shortest phase of cell cycle) includes prophase, metaphase, anaphase, and telophase.

2

Regulation of Cell Cycle

  • CDKs
  • Cyclins
  • Cyclin-CDK complexes
  • Tumor suppressors

  • CDKs
    • 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 hypophosphorylated Rb normally inhibit G1-to-S progression
    • Mutations in these genes result in unrestrained cell division (e.g., Li-Fraumeni syndrome).

3

Cell Types

  • Permanent
  • Stable (quiescent)
  • Labile

  • 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 a short G1.
    • Most affected by chemotherapy.
    • Bone marrow, gut epithelium, skin, hair follicles, germ cells.

4

Rough endoplasmic reticulum

  • Definition
  • Nissl bodies
  • Free ribosomes

  • Definition
    • Site of synthesis of secretory (exported) proteins and of N-linked oligosaccharide addition to many proteins.
    • Mucus-secreting goblet cells of the small intestine and antibody-secreting plasma cells are rich in RER.
  • Nissl bodies
    • RER in neurons
    • Synthesize peptide neurotransmitters for secretion.
  • Free ribosomes
    • Unattached to any membrane
    • Site of synthesis of cytosolic and organellar proteins.

5

Smooth endoplasmic reticulum

  • Site of steroid synthesis and detoxification of drugs and poisons.
  • Lacks surface ribosomes.
  • Liver hepatocytes and steroid hormone–producing cells of the adrenal cortex and gonads are rich in SER.

6

Cell trafficking

  • Golgi
  • Endosomes 

  • Golgi
    • 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
    • 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.

7

Cell trafficking:
Inclusion cell (I-cell) disease

  • Definition
  • Findings

  • Definition
    • Inherited lysosomal storage disorder
    • Defect in phosphotransferase
      • Ž--> failure of the Golgi to phosphorylate mannose residues (i.e., decreased mannose- 6-phosphate) on glycoproteins
      • Ž--> proteins are secreted extracellularly rather than delivered to lysosomes
  • Findings
    • Results in coarse facial features, clouded corneas, restricted joint movement, and high plasma levels of lysosomal enzymes.
    • Often fatal in childhood.

8

Cell trafficking:
Signal recognition particle (SRP)

  • Abundant, cytosolic ribonucleoprotein that traffics proteins from the ribosome to the RER.
  • Absent or dysfunctional SRP -->Ž proteins accumulate in the cytosol.

9

Cell trafficking: 
Vesicular trafficking proteins

  • COPI
  • COPII
  • Clathrin

  • COPI
    • Golgi -->Ž Golgi (retrograde)
    • Golgi -->Ž ER.
  • COPII
    • Golgi -->Ž Golgi (anterograde)
    • ER -->Ž Golgi.
  • Clathrin
    • Trans-Golgi Ž--> lysosomes
    • Plasma membrane Ž--> endosomes (receptor-mediated endocytosis [e.g., LDL receptor activity]).

10

Peroxisomes & proteasomes

  • Perioxisome
  • Proteasome

  • Peroxisome
    • Membrane-enclosed organelle involved in catabolism of very-long-chain fatty acids, branched-chain fatty acids, and amino acids.
  • Proteasome
    • Barrel-shaped protein complex that degrades damaged or ubiquitin-tagged proteins.
    • Defects in the ubiquitin-proteasome system have been implicated in some cases of Parkinson disease.

11

Microtubule

  • Structure
  • Molecular motor proteins
  • Drugs that act on microtubules

  • Structure
    • Cylindrical structure composed of a helical array of polymerized heterodimers 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.
    • ƒƒDynein = retrograde to microtubule (+ Ž--> -).
    • Kinesin = anterograde to microtubule (- Ž--> +).
  • Drugs that act on microtubules (Microtubules Get Constructed Very Poorly)
    • ƒƒMebendazole (anti-helminthic)
    • ƒƒGriseofulvin (anti-fungal)
    • ƒƒColchicine (anti-gout)
    • ƒƒVincristine/Vinblastine (anti-cancer)
    • ƒƒPaclitaxel (anti-cancer)

12

Cilia

  • Cilia structure
  • Axonemal dynein
  • Kartagener syndrome (1° ciliary dyskinesia)

  • Cilia structure
    • 9 + 2 arrangement of microtubules [A].
  • Axonemal dynein
    • ATPase that links peripheral 9 doublets and causes bending of cilium by differential sliding of doublets.
  • Kartagener syndrome (1° ciliary dyskinesia)
    • Immotile cilia due to a dynein arm defect. 
    • Results in male and female infertility due to immotile sperm and dysfunctional fallopian tube cilia, respectively
    • ↑ risk of ectopic pregnancy.
    • Can cause bronchiectasis, recurrent sinusitis, and situs inversus (e.g., dextrocardia on CXR).

13

Cytoskeletal elements & plasma membrane composition

  • Cytoskeletal elements
    • Actin and myosin
    • Microtubule
    • Intermediate filaments
  • Plasma membrane composition

  • Cytoskeletal elements
    • Actin and myosin
      • Muscle contraction, microvilli, cytokinesis, adherens junctions.
      • Actins are long, structural polymers.
      • Myosins are dimeric, ATP-driven motor proteins that move along actins.
    • Microtubule
      • Movement.
      • Cilia, flagella, mitotic spindle, axonal trafficking, centrioles.
    • Intermediate filaments
      • Structure.
      • Vimentin, desmin, cytokeratin, lamins, glial fibrillary acid proteins (GFAP),
        neurofilaments.
  • Plasma membrane composition
    • Asymmetric lipid bilayer.
    • Contains cholesterol, phospholipids, sphingolipids, glycolipids, and proteins.
    • Fungal membranes contain ergosterol.

14

Immunohistochemical stains for intermediate filaments: Cell types stained by...

  • Vimentin
  • Desmin
  • Cytokeratin
  • GFAP
  • Neurofilaments

  • Vimentin
    • Connective tissue
  • Desmin
    • Muscle
    • DesMin: Muscle
  • Cytokeratin
    • Epithelial cells
  • GFAP
    • Neuroglia
    • GFAP: NeuroGlia
  • Neurofilaments
    • Neurons

15

Sodium-potassium pump

  • Definition
  • Regulation

  • Definition
    • Na+-K+ ATPase is located in the plasma membrane with ATP site on cytosolic side.
    • For each ATP consumed, 3 Na+ go out and 2 K+ come in.
  • Regulation
    • Ouabain inhibits by binding to K+ site.
    • Cardiac glycosides (digoxin and digitoxin) directly inhibit the Na+-K+ ATPase, which leads to indirect inhibition of Na+/Ca2+ exchange --> increased [Ca2+]i --> increased cardiac contractility.

16

Collagen

  • Definition
  • Type I
  • Type II
  • Type III
  • Type IV

  • Collagen
    • Most abundant protein in the human body.
    • Extensively modified by posttranslational modification.
    • Organizes and strengthens extracellular matrix.
    • Be (So Totally) Cool, Read Books.
  • Type I
    • Most common (90%)—Bone (made by osteoblasts), Skin, Tendon, dentin, fascia, cornea, late wound repair.
    • Decreases production in osteogenesis imperfecta type I.
    • Type I: bone.
  • Type II
    • Cartilage (including hyaline), vitreous body, nucleus pulposus.
    • Type II: cartwolage.
  • Type III
    • Reticulin—skin, blood vessels, uterus, fetal tissue, granulation tissue.
    • Type III: deficient in the uncommon, vascular type of Ehlers-Danlos syndrome (ThreE D).
  • Type IV
    • Basement membrane, basal lamina, lens.
    • Defective in Alport syndrome
    • Targeted by autoantibodies in Goodpasture syndrome.
    • Type IV: under the floor (basement membrane).

17

Collagen synthesis and structure:
Inside fibroblasts

  • Inside fibroblasts
    1. Synthesis 
    2. Hydroxylation 
    3. Glycosylation 
    4. Exocytosis 
  • Outside fibroblasts
        5.  Proteolytic processing
        6.  Cross-linking

  1. Synthesis (RER)
    • Translation of collagen α chains (preprocollagen)
      • Usually Gly-X-Y (X and Y are proline or lysine).
    • Glycine content best reflects collagen synthesis (collagen is 1⁄3 glycine).
  2. Hydroxylation (RER)
    • Hydroxylation of specific proline and lysine residues
    • Requires vitamin C
      • Deficiency Ž--> scurvy.
  3. Glycosylation (RER)
    • 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 triple helix -->Ž 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. Cross-linking
    • Reinforcement of many staggered tropocollagen molecules by covalent lysine-hydroxylysine cross-linkage (by Cu2+-containing lysyl oxidase) to make collagen fibrils.
    • Problems with cross-linking Ž--> Ehlers-Danlos.

18

Osteogenesis imperfecta

  • Definition
  • Findings

  • Definition
    • Genetic bone disorder (brittle bone disease [A]) caused by a variety of gene defects.
    • Most common form is autosomal dominant with decreased production of otherwise normal type I collagen.
    • May be confused with child abuse.
  • Findings
    • ƒƒMultiple fractures with minimal trauma
      • May occur during the birth process
    • Blue sclerae [B] due to the translucency of the connective tissue over the choroidal veins
    • ƒƒHearing loss (abnormal ossicles)
    • ƒƒDental imperfections due to lack of dentin

19

Ehlers-Danlos syndrome

  • Definition
  • Types
  • Hypermobility type 
  • Classical type 
  • Vascular type 

  • Definition
    • Faulty collagen synthesis causing hyperextensible skin, tendency to bleed (easy bruising), and hypermobile joints.
  • Types
    • 6+ types.
    • Inheritance and severity vary.
    • Can be autosomal dominant or recessive.
    • May be associated with joint dislocation, berry and aortic aneurysms, organ rupture.
  • Hypermobility type
    • Joint instability
    • Most common type.
  • Classical type
    • Joint and skin symptoms
    • Caused by a mutation in type V collagen.
  • Vascular type
    • Vascular and organ rupture
    • Deficient type III collagen.

20

Menkes disease

  • Connective tissue disease caused by impaired copper absorption and transport.
  • Leads to decreased activity of lysyl oxidase (copper is a necessary cofactor).
  • Results in brittle, “kinky” hair, growth retardation and hypotonia.

21

Elastin

  • 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-linking takes place extracellularly and gives elastin its elastic properties.
  • Broken down by elastase, which is normally inhibited by α1-antitrypsin.

22

Elastin

  • Marfan syndrome
  • Emphysema
  • Wrinkles of aging

  • Marfan syndrome
    • Caused by a defect in fibrillin, a glycoprotein that forms a sheath around elastin.
  • Emphysema
    • Can be caused by α1-antitrypsin deficiency, resulting in excess elastase activity.
  • Wrinkles of aging
    • Due to decreased collagen and elastin production.

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