Biochem - First Aid 2014

Front 1

Describe the general sequence of the cell cycle.

Back 1

After mitosis, the cell cycle enters the G1 phase (growth phase 1). At this point, non proliferating cells enter G0 (quiescent phase), whereas active cells proceed to the synthesis phase (DNA replication). After S phase, G2 will occur for a short period before the cell divides again.

Front 2

Describe the G1 Checkpoint.

Back 2

end of G1 phase

Most eukaryotic cells decide whether to proceed with DNA replication (S phase) or become quiescent (G0); depends on availability of nutrients, DNA damage and surrounding conditions.

Checkpoint largely dependent on p53 (determines if cell can go to S phase or G0)

Front 3

What are pathologies associated with G1 Checkpoint defects?

Back 3

Tumor suppressor genes:

p53-- chromosome 17p = Li-Fraumeni syndrome

Rb--chromosome 13q = retinoblastoma and osteosarcoma

Front 4

Describe the G2 Checkpoint.

Back 4

end of G2, just before mitosis

Two crucial molecules involved:

Maturation promoting factor (MPF)

Cyclindependent kinase (CDK)

Front 5

Describe the M Checkpoint.

Back 5

takes place in anaphase

action of CDK-1 triggers the destruction of cyclins, causing the cell to exit mitosis and enter cytokinesis

Front 6

Regulation of Cell Cycle:

CDKs (cyclin dependent kinases)

Back 6

constitutive and inactive

A Cdks is an enzyme that adds negatively charged phosphate groups to other molecules in a process called phosphorylation. Through phosphorylation, Cdks signal the cell that it is ready to pass into the next stage of the cell cycle. As their name suggests, Cyclin-Dependent Protein Kinases are dependent on cyclins, another class of regulatory proteins. Cyclins bind to Cdks, activating the Cdks to phosphorylate other molecules.

Front 7

Regulation of Cell Cycle:

Cyclins

Back 7

regulatory proteins that control cell cycle events; phase specific; activate CDKs

Cyclins are named such because they undergo a constant cycle of synthesis and degradation during cell division. When cyclins are synthesized, they act as an activating protein and bind to Cdks forming a cyclin-Cdk complex. This complex then acts as a signal to the cell to pass to the next cell cycle phase. Eventually, the cyclin degrades, deactivating the Cdk, thus signaling exit from a particular phase.

Front 8

Regulation of Cell Cycle:

Cyclin-CDK complexes

Back 8

must be both activated and inactivated for cell cycle to progress

Front 9

Regulation of Cell Cycle:

Tumor Supressors

Back 9

p53 and hypophosphorylated Rb

both normally inhibit G1 to S progression; mutations in these genes result in unrestrained cell division. (i.e. Li-Fraumeni Syndrome)

Front 10

Describe a permanent cell and give examples.

Back 10

Remain in G0, regenerate from stem cells

neurons, skeletal and cardiac muscle, RBCs

Front 11

Describe a stable (quiescent) cell and give examples.

Back 11

Enter G1 from G0 when stimulated.

Hepatocytes, lymphocytes

Front 12

Describe a labile cell and give examples.

Back 12

Never go to G0, divide rapidly with a short G1.

Most affected by chemotherapy.

Bone marrow, gut epithelium, skin, hair follicles, germ cells

Front 13

What is the function of rough endoplasmic reticulum?

Back 13

site of synthesis of secretory (exported) proteins and of N-linked oligosaccharide addition to many proteins

Front 14

What are Nissl bodies?

Back 14

RER in neurons

synthesize neurotransmitters for secretion

Front 15

What is the function of free ribosomes?

Back 15

site of synthesis of cytosolic and organellar proteins

Front 16

What cell types are rich in RER?

Back 16

mucus-secreting goblet cells of small intestine

antibody-secreting plasma cells

Front 17

What is the function of Smooth ER?

Back 17

site of steroid synthesis and detoxification of drugs and poisons. Lacks surface ribosomes.

Front 18

What cell types are rich in Smooth ER?

Back 18

liver hepatocytes

steroid hormone producing cells of adrenal cortex and gonads

Front 19

Golgi is the distribution center for proteins and lipids from ER to the vesicles and plasma membrane.

List the modifications the Golgi makes on amino acids and proteins.

Back 19

modifies N-oligosaccharides on asparagine

adds O-oligosaccharides on serine and threonine

adds mannose-6-phosophate to proteins for trafficking to lysosomes

Front 20

What is the function of endosomes.

Back 20

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

Front 21

What is the pathology of I-Cell Disease?

(MPS type 2)

Back 21

I-cell disease is an autosomal recessive disorder caused by a deficiency of GlcNAc phosphotransferase, which phosphorylates mannose residues on glycoproteins within the Golgi apparatus. Without mannose-6-phosphate to target them to the lysosomes, the enzymes are transported from the Golgi to the extracellular space, resulting in large intracellular inclusions of molecules requiring lysosomal degradation in patients with the disease.

The presence of lipids, glycosaminoglycans (GAG's) and carbohydrates in the blood provide for the distinguishing characteristic to separate I-Cell from Hurlers Syndrome, in Hurlers, only glycosaminoglycans would be present

Front 22

What are the clinical findings in I-Cell disease?

Back 22

failure to thrive

coarse facial features

* High, narrow forehead
* Puffy eyelids, epicanthal folds
* Flat nasal bridge, anteverted nares
* gingival hypertrophy
* macroglossia

tubular bones of UE are short and wide; while phalanges are bullet-shaped

restricted joint movement

clouded corneas

high plasma levels of lysosomal enzymes

Front 23

What is a Signal recognition particle (SRP) ?

What occurs when SRP is absent?

Back 23

abundant, cytosolic ribonucleoprotien that traffics proteins from the ribosome to the RER.

absent or dysfunctional SRP = proteins accumulate in the cytosol

Front 24

Discuss the three types of vesicular trafficking proteins:

COP1

COP2

Clathrin

Back 24

COP1: Golgi to Golgi (retrograde); Golgi to ER

COP2: Golgi to Golgi (anterograde); ER to Golgi

Clathrin: trans-Golgi to lysosomes; plasma membrane to endosomes (receptor-mediated endocytosis--i.e. LDL receptor activity)

Front 25

What is the function of peroxisomes?

Back 25

membrane-enclosed organelle involved in catabolism of very-long chain fatty acids; branched chain fatty acids and, amino acids

Front 26

What is the function of proteasome?

Back 26

Barrel-shaped protein complex that degrades damaged or ubiquitin-tagged proteins.

Defects in ubiquitin-proteasome system have been implicated in some cases of Parkinson disease

Front 27

Describe the structure of microtubules.

Back 27

Cylindrical structure composed of a helical array of polymerized heterodimers of alpha and beta tubulin. Polymerization occurs slowly from positive end, but depolarization occurs rapidly without a GTP cap in place.

Each dimer has 2 GTP bound.

Incorporated into flagella, cilia and mitotic spindles.

Also involved in slow axoplasmic transport in neurons.

Front 28

Describe the molecular motor proteins involved in transporting cellular cargo toward opposite ends of microtubule tracks.

Back 28

transport various cellular cargo by walking on microtubules in their respective directions:

dynein = retrograde to microtubule

(+ end to - end)

kinesin = anterograde to microtubule (- end to + end)

Front 29

Drugs that target microtubules:

Back 29

Microtubules Get Constructed Very Poorly

Mebendazole (anti-helminthic)
Griseofulvin (anti-fungal)

Colchicine (anti-gout)
Vincristine/Vinblastine (anti-cancer)

Paclitaxel (anti-cancer)

Front 30

Describe the structure of cilia.

What is axonemal dynein?

Back 30

9 + 2 arrangement of microtubules.

Axonemal dyne in—an ATPase that links peripheral

9 doublets and causes bending of cilium by differential sliding of doublets.

Front 31

Describe Kartagener syndrome and its clinical findings.

Back 31

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).

Front 32

Cytoskeletal element:

Describe intermediate filaments

Back 32

Structure. Vimentin, desmin, cytokeratin, lamins, glial fibrillary acid proteins (GFAP), neurofilaments.

intermediate filaments are extremely stable. Even after extraction with solutions containing detergents and high concentrations of salts, most intermediate filaments in a cell remain intact, whereas microfilaments and microtubules depolymerize into their soluble subunits

Front 33

What is the composition of plasma membranes.

Back 33

Asymmetric lipid bilayer.

Contains cholesterol, phospholipids, sphingolipids, glycolipids, and proteins.

Fungal membranes contain ergosterol.

Front 34

List the immunohistochemical stains for intermediate filaments (stain and cell type):

Back 34

Vimentin -- Connective Tissue

DesMin -- Muscle

Cytokeratin -- Epithelial cells

GFAP -- NeuroGlia

Neurofilaments -- Neurons

Front 35

Describe the Sodium Potassium ATPase pump.

Back 35

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.

Front 36

Describe the interaction of compounds with the Na/K pump and how it inhibits this pump's activity.

Back 36

Ouabain inhibits by binding to K+ site.

Cardiac glycosides (digoxin and digitoxin)

directly inhibit the Na+-K+ ATPase (mainly in myocardium), which leads to indirect inhibition of Na+/ Ca2+ exchange. Without Ca being pumped out of cell, this increases intracellular Ca, which results in increase in cardiac contractility.

Front 37

What is collagen?

Back 37

Most abundant protein in the human body. Extensively modified by posttranslational

modification.
Organizes and strengthens extracellular matrix.

Front 38

Describe the structure of collagen.

Back 38

consists of three polypeptide chains (alpha chains) wound around each other to form a long, stiff triple helical structure.

collagen is glycine and proline rich with glycine present at every third amino acid.

GLY-X-Y = X & Y can be any amino acid,

but X is commonly proline and

Y is commonly hydroxyproline

different alpha chain compositions in the various types of collagen

Front 39

What does type 1, 2, 3, 4 and 10 collagen constitute in the body?

Back 39

Be (So Totally) Cool, Read Books.

type 1 = Most common (90%)—Bone (made by osteoblasts), Skin, Tendon, dentin, fascia, cornea, late wound repair.

type 2 = Cartilage (including hyaline), vitreous body, nucleus pulposus.

type 3 = Reticulin—skin, blood vessels, uterus, fetal tissue, granulation tissue.

type 4 = Basement membrane, basal lamina, lens.

type 10 = epiphyseal plate

Front 40

Describe the process of collagen being laid down during wound healing.

Back 40

Wound healing: Type 3 to Type 1

Three: owie (just scraped your knee)

One: it's all done

Type 3 collagen is laid down first in granulation tissue. As healing progresses, fibroblasts secrete type 1 collagen, which eventually replaces type 3 collagen in late wound repair.

Front 41

Describe collagen synthesis "inside" the fibroblast.

Back 41

Nucleus:

1. Formation of alpha chains mRNA (preprocollagen) in nucleus.

2. Nuclear export of preprocollagen mRNA followed by entry into rough ER.

RER:

3. SYNTHESIS of preprocollagen alpha chains with registration sequence (responsible for quaternary structure) by ribosomes

4. HYDROXYLATION of proline and lysine catalyzed by peptidyl proline hydroxylase and peptidyl lysine hydroxylase, respectively.

5. GLYCOSYLATION of hydroxylysine residues

6. Formation of alpha chain triple helix = procollagen

Golgi:

7. addition of carbohydrates

8. packaging into vesicles and movement to plasma membrane for exocytosis of procollagen.

Front 42

Describe collagen synthesis "outside" the fibroblast.

Back 42

1. PROTEOLYTIC PROCESSING: Procollagen peptidase cleave registration sequences (disulfide-rich terminal regions) of procollagen to form insoluble tropocollagen

2. CROSS-LINKING: Reinforcement of many staggered tropocollagen molecules by covalent lysine-hydroxylysine cross-linkage (by Cu2+-containing lysyl oxidase) to make collagen fibrils

Front 43

Which aspect of collagen synthesis requires Vitamin C?

Back 43

hydroxylation of proline and lysine

Front 44

Describe the pathology of Scurvy.

Back 44

Vitamin C deficiency

results in inability to hydroxylate proline and lysine resides in alpha chain polypeptides of collagen molecules

Causes weakening of capillaries:

ulceration and bleeding gums

loose teeth (due to loss of periodontal ligaments, which are collagen rich)

tissue hemorrhage

anemia

poor wound healing

impaired bone formation (during growth)

Front 45

Describe the genetics and cellular characteristics of Osteogenesis Imperfecta.

Back 45

most common form is autosomal dominant -- variety of gene defects cause deficiency in production of type 1 collagen

--deficiency arises from an amino acid substitution of glycine to bulkier amino acids in the collagen triple helix structure

leads to either less collagen or less functional collagen = weak or brittle bones

Front 46

Describe the clinical finding of Osteogenesis Imperfecta.

Back 46

Multiple fractures with minimal trauma;

may occur during the birth process; may be confused with child abuse

Blue sclerae due to the translucency of

the connective tissue over the choroidal

veins

Hearing loss (abnormal ossicles)

Dental imperfections due to lack of dentin (defects in enamel synthesis = amelogenesis imperfecta)

Front 47

XRay in osteogenesis imperfecta.

Back 47

Front 48

Although there are four types: Contrast Type 1 and Type 2 osteogenesis imperfecta.

Back 48

Type I

* Most common and mildest type of OI.
* Bones fracture easily. Most fractures occur before puberty.
* Normal or near-normal stature.
* Loose joints and muscle weakness.
* Sclera (whites of the eyes) usually have a blue, purple, or gray tint.
* Triangular face.
* Tendency toward spinal curvature.
* Bone deformity absent or minimal.
* Brittle teeth possible.
* Hearing loss possible, often beginning in early 20s or 30s.
* Collagen structure is normal, but the amount is less than normal.
* Most severe form.
* Frequently lethal at or shortly after birth, often due to respiratory problems.
* Numerous fractures and severe bone deformity.
* Small stature with underdeveloped lungs.
* Tinted sclera.
* Collagen improperly formed.

Front 49

Describe the pathology of Ehlers-Danlos Syndrome.

Back 49

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 and aortic aneurysms, organ rupture.

Front 50

Describe the hyper mobility type of Ehlers-Danlos syndrome.

Back 50

(joint instability): most common type.

usually least severe

Front 51

Describe the classic type of Ehlers-Danlos syndrome.

Back 51

(joint and skin symptoms): characterized by skin hyperelasticity, joint hypermobility, increased tendency to bruise, and abnormal cigarette paper scarring.

Mutations in type V collagen (a regulator of type I collagen fibrillogenesis).

Front 52

Describe the vascular type of Ehlers-Danlos syndrome.

Back 52

(vascular and organ rupture): deficient type III collagen

ie. colon, large blood vessels and gravid uterus are rich in type 3 collagen

Front 53

Describe the pathology of Epidermolysis Bullosa.

Back 53

Absence of Type 7 collagen

Type 7 collagen is responsible for formation of anchoring fibrils between dermis and epidermis (anchor basement membrane to underlying dermis)

This results in paper thin skin (called "butterfly children": because their skin is as delicate as butterfly wings)

Front 54

Describe the pathology of Menkes disease.

Back 54

Connective tissue disease caused by impaired copper absorption and transport.

Leads to decrease activity of lysyl oxidase (copper is a necessary cofactor) = decrease cross linking

Results in brittle, “kinky” hair, growth retardation and hypotonia.

Front 55

Define the term argyrophilic.

Back 55

silver loving:

reticular fibers (type 3 collagen molecules) are recognized by silver stain

Front 56

Describe the pathology of Goodpasture syndrome.

Back 56

antibodies against glomerular basement membrane as well as antibodies against basement membrane of lung tissue: bind to type 4 collagen

leads to glomerulonephritis and pulmonary hemorrhage

Front 57

Describe the pathology of Alport syndrome.

Back 57

Mutation in type IV collagen: thinning and splitting of the glomerular basement membrane. Most commonly X-linked.

Glomerulonephritis, deafness, and, less commonly, eye problems (cataracts/anterior lenticonus).

Front 58

Elastic fibers consist of what two structural components?

As elastic fibers allow tissues to stretch and distend, give examples of where these fibers are located.

When elastin proteins are cross linked into elastic fiber network, their collective coil properties allow the network to be stretched and recoil like a rubber band.

Back 58

elastin and surrounding fibrillin microfibrils

vertebral ligaments (ligamentum flava; ligamentum nuchae)

vocal folds of larynx

elastic arteries

skin

lung

Front 59

Elastin is a highly hydrophobic protein that is rich in ____________________; elastin is poor in _________ and lacks ________________.

Back 59

rich in glycine and proline (like collagen)

poor in hydroxyproline

lacks hydroxylysine

Front 60

Elastin is normally broken down by ___________, which is normally inhibited by _______________.

Back 60

elastase

alpha-1-antitrypsin

Front 61

Elastin synthesis parallels collagen synthesis within fibroblasts and Smooth muscle cells.

What are the two main steps of elastin synthesis?

Back 61

1. secretion of tropoelastin (elastin precursor)

2. cross-linking of tropoelastin molecules via their two unique amino acids (desmosine and isodesmosine) to form extensive networks of elastin fibers and sheets (also requires lysyl oxidase for cross-linking)

Front 62

Describe Fibrillin-I glycoprotein.

Back 62

a major component of the microfibrils that form a sheath surrounding the amorphous elastin (provides a scaffold for deposits of elastin molecules).

It is believed that the microfibrils are composed of end-to-end polymers of fibrillin.

Front 63

Describe the mechanism of lysyl oxidase .

Back 63

An extracellular copper enzyme that catalyzes formation of aldehydes from lysine residues (called allysine) in collagen and elastin precursors.

These aldehydes are highly reactive, and undergo spontaneous chemical reactions with other lysyl oxidase-derived aldehyde residues, or with unmodified lysine residues. This results in cross-linking collagen and elastin, which is essential for stabilization of collagen fibrils and for the integrity and elasticity of mature elastin

Front 64

Give an example of how a copper deficiency would affect biologic structures.

Back 64

dissecting aneurisms of blood vessels due to incomplete elastin cross-linking

Front 65

Describe the genetic and cellular characteristics of Marfan Syndrome.

Back 65

autosomal dominant

Gene:

fibrillin gene (FBN1)

elastin-associated fibrillin microfibrils are absent; results in formation of abnormal elastic tissue

Front 66

Describe the clinical features of Marfan Syndrome

Back 66

Bone elongation (tall individuals with long, thin limbs)

Spider-like fingers (arachnodactyly)

Hypermobile joints

Lens dislocation (glaucoma and retinal detachment also common)

Cardiac abnormalities (mitral valve prolapse is common)

Aortic rupture--most common cause of death (due to loss of elastic fibers in tunica media)

Front 67

What is the pathologic relationship of emphysema and elastin.

Back 67

can be caused by α1-antitrypsin deficiency, resulting in excess elastase activity

Front 68

What are wrinkles caused by?

Back 68

Wrinkles of aging are due to decrease in collagen and elastin production

Front 69

Glycosaminoglycans (GAGs) are long polysaccharide chains composed of repeating disaccharide units. Describe what these repeating units consist of.

Back 69

One of the disaccharide units is always an amino sugar (N-acetylglucosamine or N-acetylgalactosamine)

The second sugar is usually an uronic acid (glucuronic acid or iduronic acid)

Front 70

Why are GAGs the most negatively charged molecules produced by animal cells?

What is the purpose of their negative charge?

Back 70

sulfate and carboxyl groups present on most of their sugars

These highly negatively charged molecules are essential for maintaining the water content present in ground substance.

Front 71

5 Types of GAGs found in human body:

Describe hyaluronic acid.

Back 71

unsulfated

provide attachment sites of core proteins to form proteoglycan aggregates

Front 72

5 Types of GAGs found in human body:

Location of Chondroitin sulfate

Back 72

cartilage, bone, heart valves

Front 73

5 Types of GAGs found in human body:

Location of Keratin sulfate.

Back 73

cartilage, bone, cornea, intervertebral disk

Front 74

5 Types of GAGs found in human body:

Location of DermatAn sulfate

Back 74

dermis of skin, blood vessels, heart valves

Front 75

5 Types of GAGs found in human body:

Location of HeparAn sulfate

Back 75

basal lamina, lung and liver