Biochem/cell cycles/etc etc etc Flashcards
Codominance definition and example
Both alleles contribute to phenotype of heterozygote
Ex: A/B/AB blood groups, a1-antitrypsin def, HLA groups
Variable expressitivity definition and example
Pts with same genotype dont always have same phenotype
Ex: 2 pts with neurofibromastosis type I may have varying disease severity
Incomplete penetrance definition and example
Not all ppl with mutant genotype show mutant phenotype (% penetrance x probability of inheriting gene = risk)
Ex: BRCA1 genes dont always cause breast or ovarian cancer
Pleiotropy definition and example
One gene contributes to multiple phenotypic effects
Ex: untreated phenylketonuria (PKU) manifests with light skin, intellectual disability, and musty body odor
Anticipation definition and example
Increased severity or earlier onset of disease in succeeding generations
Ex: trinucleotide repeat diseases (hungtinton)
Loss of heterozygosity definition and example
If a patient inherits or develops a mutation in a tumor suppressor gene, the complementary allele must be deleted/mutated before cancer develops. This is not true of oncogenes.
Ex: retinoblastoma and the “two hit hypothesis”, lynch syndrome (HNPCC), li-fraumeni syndrome
Dominant negative mutation definition and example
Exerts a dominant effect. Heterozygote produces a non-functional altered protein that also prevents the normal gene product from functioning.
Ex: mutation of a TF in its almost eric site. Non functioning mutant can still bind to DNA, preventing wild type TF from binding.
Linkage disequilibrium definition
Tendency for alleles at 2 linked loci to occur together more/less often than chance predicts. Measured in populations, not family, varies by population.
Mosaicism definition and example
Presence of genetically distinct cell lines in the same individual
Ex: McCune Albright syndrome
Locus heterogeneity definition and example
Mutation at different loci can product a similar phenotype
Ex: albinism
Alleles heterogeneity definition and example
Different mutations in same locus produce same phenotype
Ex: beta-thalassemia
heteroplasmy definition and example
Presence of both normal and mutated mtDNA, resulting in variable expression in mitochondrially inherited disease
Ex: mtDNA passed from mother to all children
Uniparental Disomy definition and example
Offspring receives 2 copies of a chromosome from 1 parent, and none from the other parent.
Ex: consider in a pt with a recessive disorder when only one parent is a carrier, such as prader-willi and Angelina syndromes
Hardy Weinberg law assumptions include
No factors altering genetic selection:
No mutation occurring at locus
Natural selection is not occurring
Completely random mating
No net migration
What does the hardy weinburg equilibrium represent?
Hypothetical state of balance in a population where the frequency of dominant and recessive alleles is the same from one generation to the next
What is genetic drift
Small lot = greater risk of losing alleles from one generation to next because not everyone reproduces
The process of making new gametes is
Meiosis
Define independent assortment
Alleles inherited for one trait (such as eye color) don’t affect those for another (such as hair color)
Define crossing over
In meiosis, homogolous chromosomes exchange equivalent parts of themselves that carry the same types of genes
What is genetic linkage
Chance that 2 genes are inherited together depends on the distance separating them; common exemption to law of independent assortment
For 2 genes to be linked:
Chance of ending up on different gametes <50%
Parental vs recombinant gamete’s
Parental - linked genes inherited together
Recombinant - crossing over separated linked genes
The cell cycle is regulated by:
Cyclins
Cyclin-dependent kinases
Cyclin-CDK complexes
Tumor suppressors
What are cyclins?
Regulatory proteins that control cell cycle events; phase specific, activate CDKs
What do cyclin-CDK complexes do
Phosphorylate other proteins to coordinate cell cycle progression; must be activated and inactivated at appropriate times for cell cycle to progress
What do tumor suppressors do?
P53 induces p21 which inhibits CDKs
>hypophosphorylatoin (activation) of Rb
>inhibition of G1-S progression
Mutations in tumor suppressor genes can result in unrestrained cell division (eg Li-Fraumeni syndrome)
GF (eg insulin, PDGF, EPO, EGF) bind tyrosine kinase receptors to transition the cell from G1 to S phase
What is the shortest phase of the cell cycle
M phase
M phase includes:
Mitosis and cytokinesis
Stages of mitosis
Prophase
Prometaphase
Metaphase
Anaphase
Telophase
what is cytokinesis?
Cytoplasm splits in two
Phases of cell cycle
M phase (mitosis and cytokinesis)
G0
G1
S
G2
Interphase
Permanent cells definition and examples
Remain in G0, regenerate from stem cells
Neurons, skeletal and cardiac muscle, RBCs
Stable (quiescent) cells definition and examples
Enter G1 from G0 when stimulated
Hepatocytes, lymphocytes, PT, periosteal cells
Labile cells definition and examples
Never go to G0, divide rapidly with a short G1. Most affected by chemo
Bone marrow, gut epithelium, skin, hair follicles, germ cells
Rough ER cells definition and examples
Site of synthesis of secretory (exported) proteins and N linked oligosaccharide addition to lysosomal and other proteins
Nissl bodies (RER in neurons) - synthesize peptide NTs for secretion
Freee ribosomes - unattached to any membrane, site of synthesis of cytosolic, Pedro is Al, and mitochondrial proteins
Mucus secreting goblet cells of small intestine, antibody secreting plasma cells rich in RER
Smooth ER cells definition and examples
Site of steroid synthesis and detox of drugs and poisons. Lacks surface ribosomes.
Liver hepatocytes and steroid hormone-producing cells of the adrenal cortex and gonads rich in SER
What cells go through cell cycle?
All except reproductive; varies in length
Cell cycle phases
Interphase
Mitosis
Interphase v mitosis
Interphase:
Long
State of prep
Cell performs basic functions
Grow and replicates DNA
Mitosis:
Cellular division
Interphase subphases
G1 - gap or growth 1 (longest): growth, organelles synthesize proteins and produce energy. Chromosomes are chromatids.
G1 checkpoint - checks for damaged DNA, right proteins. safe to divide?
G0 - repair issues
S - synthesis, DNA replication
Structural proteins, enzymes, energy
G2 - gap/growth 2; duplicate organelles for daughter cells
G2 checkpoint
Mitosis subphases
Divides into two daughter cells
Separates DNA to two nuclei > karyokinese
Separate daughter cells > cytokinesis
Please Make Another Two Cells
Prophase - nuclear membrane disintegrates, chromosomes condense
Metaphase - chromosomes > middle
Anaphase - centromeres pull sister chromatids apart
Telophase - nuclear membrane reforms
Cytokinesis cell membrane pinches, daughter cells separate
Cell signaling classification
Autocrine: from cell to own receptors
Paracrine: to target cells nearby
Endocrine: to target cells further away
Signaling molecules are called
Ligands
What ligands need carrier proteins?
Hydrophobic ones
What ligands need transmembrane receptors?
Hydrophilic
Stages of cell signaling pathways
- Reception - receptors bind to ligand
- Transduction - receptor protein changes, activates intracellular molecules (2nd messengers)
- Cells response to signal
3 major classes of transmembrane receptors
G protein coupled
Enzyme coupled
Ion channel
G protein couple receptors
7 pass transmembrane receptors
Bind to GDP when inactive, GTP when active > alpha subunit separates and converts GTP > GDP to turn it off
G protein types
Gq
Gi
Gs
Protein Gq actions
activates phospholipase C in cell membrane > cleaves phosphytidylinositol 4,5-biphosphate into
>DAG; remains attached to membrane, binds to kinase C (relies on Ca to activate) > activates protein by adding phosphoryl groups to them
>inositol triphosphate; soluble, diffuses freely through cytoplasm and into ER where it opens Ca channels > [Ca] higher in ER, flows out to cytoplasm > depolarization of cell
Ca out of ER to cytoplasm > depolarization
Protein Gs
Stimulates enzyme adenylate cyclase, removes 2 phosphates from ATP > cAMP
cAMP moves throughout cytoplasm and binds to protein kinase A regulatory subunit > regulatory subunit dissociates from catalytic subunit > catalytic subunit phosphorylates target proteins that trigger a cellular response
Protein G1
Bound to adenylate cyclase (inhibits in) > neg feedback protein Gs, inactivates cells
Enzyme coupled receptors
Single pass transmembrane proteins
Intrinsic enzyme activity
Two parts with different functions: receptor domain
enzyme domain - usually a protein kinase that phosphorylates receptor domain
Receptor tyrosine kinases
most common, many subfamilies. Can’t phosphorylate own tyrosine side chains.
Ligands bind > two receptor chains dimerize > cross phosphorylate each other at multiple tyrosine residues > high affinity binding sites for second messengers (can be phosphorylated and activated) > triggers signaling
types of enzyme coupled receptors
Based on amino acid at which receptor is phosphorylated
Receptor tyrosine kinases
Tyrosine kinase associated receptors
Receptor serine/threonine kinases
Tyrosine kinase associated receptors
Work similarly to receptor tyrosine kinases but they have no intrinsic enzyme activity. Associated with cytoplasm is tyrosine kinases.
When receptors bind their ligand, cytoplasm tyrosine kinases phosphorylate various target proteins to relay the signal
Receptor serene/threonine kinase
Serine/threonine kinase domain on intracellular end. Two classes: type 1 and type 2, structurally similar.
Ligand binding brings type I and type II receptors together so that the type II receptor can phosphorylate and activate the type I receptor > type I recruits and phosphorylates various target proteins to relay the signal
Ion channel receptors
Generally closed
Open once they bind a specific ligand
Allow ions like Cl-, Ca2+, Na+, and K+ to passively flow down their gradient > shift in charge distribution inside cell > cellular response
Cell membrane components
Barrier of 2x lipids + protein and carbs
Categories of molecular studies trying to cross membrane
Small + non-polar (O2, CO2) - able to diffuse rapidly through membrane
Small polar like water - can cross slowly
Large, non polar like Vit A - slow to cross
Large polar like glucose, and highly polar ions like Na, K, Cl and charged like amino acids - highly unlikely to get across cell membrane on their own
Examples of transport proteins
Channels like aquaporins and chloride channels
Carriers like glucose transporter
Do endocytosis and exocytosis need energy?
Both need adenosine triphosphate (ATP)
Types of endocytosis
Phagocytosis
Pinocytosis
Receptor mediated endocytosis
Phagocytosis
Used by WBC like macrophages and neutrophils
> phagosome
Electron pump uses ATP into phagosome > lowers pH
Phagosome and lysosome fuse, forming phagolysosome > lysosome digestive enzymes destroy bacteria in the acidic pH
Lysosome expels materials out of cell membrane into extra cellular space
Pinocytosis
“The cell drinks”
Cells plasma membrane invaginates to form a small cup around extracellular fluid and solutes not dissolved enough > edges of cup come together to form vesicle > motors proteins like kinesin or dynein use ATP to carry the vesicle deeper into the cytosol. At the same time the vesicle slowly releases the extracellular fluids and solutes into cytosol as well
Nonspecific way for cells to take in solute
Receptor mediated endocytosis
E.g. transferrin (iron binding protein), low density lipoproteins (LDLs)
On surface of cell membrane there are indented pits with receptors for the molecules. These pits are covered on intracellular side by clathrin proteins (coated pits). LDL (ex) binds to receptor > edges of pits come together > clathrin link up link sturdy shell > vesicles pinch off > clathrin detach
Inside the cell the vesicle merges with endosome (fuse with ingested vesicles, separates LDL from receptor with its ATP proton pump to lower pH) > vesicle splits into 2 (one with LDL, one with LDL receptors) > LDL vesicle > lysosome for digestion. Receptor vesicle > releases receptor on cell membrane (receptor recycling)
Exocytosis
Starts in Golgi apparatus > takes proteins, lipids, and hormones from RER and SER > packages in vesicle that can be zip lined around cell using cytoskeleton (cytoskeleton is make of proteins like micro filaments, micro tubules, and intermediate filaments which all provide stability), allows cell to change shape and helps structures move from one area to another
Secretory vesicles + motor proteins > move cell along microtubules with ATP, ruptures outside membrane
vit A function
antioxidant
constituent of visual pigments
differentiation of epithelial cells > specialized tissue (pancreatic cells, mucus secreting cells)
prevents squamous metaplasia
used to treat measles and acute promyelocytic leukemia
sources of vit A
liver and leafy vegetables
vit A def
Night blindness (nyctalopia)
Dry scaly skin (xerosis cutis)
Corneal squamous metaplasia > bitot spots (foamy keratin debris on conjuntiva)
Corneal degerneration (keratomalacia)
Immunosuppression
vit A excess
Acute toxicity - N/V, vertigo, blurred vision
Chronic toxicity - alopecia, dry skin, hepatotoxicity and enlargement, arthralgias, idiopathic intracranial HTN
vit A teratogenic?
cleft palate
cardiac abnormalities
vit B1 name
thiamine
vit A name
retinol
B1 function
in thiamine pyrophosphate (TPP) - cofacactor for lots of dehydrogenase enzyme reactions
Be APT
Branched chain ketoacid d
a-ketoglutarate d (TCA)
pyruvate d (links glycolysis to TCA)
transkelotase (HMP shunt)
B1 def
impaired glucose breakdown > ATP depletion worsened by gljucose infusion, highly aerobic tissues (brain, heart) affected first
wenickle korsakoff (confusion, ophthalmoplegia, ataxia)
dry beriberi - polyneuropathy, sym muscle wasting
wet beriberi - high output CF (dilated cardiomyopathy), edema
vit B2 name
riboflavin
vit B2 function
component of FAD and FMN, used as cofactors in redox reactions, esp the succinate dehydrogenase reaction in the TCA cycle
B2 def
cheilosis (inflammation of lips, FAD/FMN fissures)
corneal vascularization
vit B3 name
niacin
B3 function
constituent of NAD+ and NADP+ (used in redox reactions)
NAD/B3 = 3 ATP
derived from tryptophan, needs B2 and B6 for synthesis
treats dyslipidemia, lowers VLDL, raises HDL
B3 def
glossitis
severe def > pellagra; sx of pellagra 3D’s - diarrhea, demetia/hallucinations, dermatitis (broad collar rash)
hyperpigmentation of exposed limbs
can be caused by hartnup disease (def of neutral amino acid)
B3 excess
podagra
facial flushing (induced by prostaglandins, not histamine)
hyperglycemia
hyperuricemia
vit B5 name
patothenic acid
vit B5 function
essential component of CoA (cofactor for acetyl transfers) and fatty acid synthase
B5 def
dermatitis
enteritis
alopecia
adrenal insufficiency
B6 name
pyridoxine
B6 function
converted to PLP, cofactor in transamination (ALT, AST) decarb rxns, hlycogen phosphorylase
synthesis of cystathionine, heme, niacin, histamine, and NTs like serotonin, epi, norepi(NE), dopamine, and GABA
B6 def
convulsinos
hyperirritability
peripheral neuropathy (induced by isoniazid and OCs)
sideroblastic anemia
B7 name
biotin
B7 function
cofactor for carboxylation enzymes, which add a 1-carbon group:
-pyruvate carboxylase: pyruvate (3C) > oxaloacetate (4C)
-acetylCoA carboxylase: acetyl CoA (2C) > malonynl CoA (3C)
-propionyl CoA carboxylase: propionylCoA (3C) > methylmalonyl-CoA (4C)
B7 def
rare
dermatitis
enteritis
alopecia
caused by long term antibiotic use or excessive ingestion of raw egg whites
adivin in egg whites avidly binds biotin
vit B9 name
folate
B9 function
converted to tetrahydrofolic acid THF, coenzyme for 1-C transfer/methylation in DNA and RNA
imp for synthesis of nitrogenous bases in DNA and RNA
sources, absoprtion, storage of B9
leafy green veggies , absorbed in jejenum, small reserve pool in liver
B9 def
macrocytic, megaloblastic anemia; hypersegmented polymorphonuclear cells (PMNs)
glossitis
no neuro sx
inc homocysteine
alcoholism and pregnancy , sulfa drugs, methotrexate
vit B12 name
cobalamin
B12 function
cofactor for methionine synthase (transfers CH3 groups as methylcobalamin)
imp for DNA synthesis
B12 sources, syntehsis, reserve
found in animal products
synthesized only by microorganisms
large, several year reserve pool in liver
causes of B12 def
malabsorption (sprue, enteritis, bacterial overgrowth, alcohol, etc)
lack of IF (pernicious anemia, gastric bypass)
absence of terminal ileum (surgery for crohns)
drugs like metformin
insufficient intake
B12 def
macrocytic, megaloblastic anemia
hypersegmented PMNs
paresthesias and subacute combined degernation due to abnormal myelin
inc serum homocysteine and methylmalonic acid
2nd degree foalte def
prolonged def > irreversible nerve damage
B1 def causes
alcohol abuse (interferes with thiamin conversion to active form and prevents absorption, cirrhosis sotrage interfereence) and malnourishment
vit C name
ascorbic acid
vit C sources
fruits and veggies
vit C function
antioxidant
facilitates iron absorption by reducing it to Fe2+ state
necessary for hydroxylation of proline and lysine in collegane synthesis
necessary for doapmine b-hydroxylase, which converts dopamine > NE
vit C def
scurvy - sweollen gums, easy bruising, petechiae, hemarthrosis, anemia, poor wound healing, perifollicular and subperiosteal hemorrhages, corkscrew hair, immunodeficiency
vit C causes sCurvy due to a Collagen synthesis defect
vit C excess
nasuea, vommiting
diarrhea
fatigue
calcium oxalate nephrolithiasis
inc iron toxiciity in predisposed individuals
vit D forms and sources
D2 (ergocalciferol) - plants, fungi, yeast
D3 (cholecalciferol) - stratam basale from sun, fish, milk, plants
both converted to 25-OH D3 (storage form) in liver and to the active form 1,25-(OH)2D3 (cacitriol) in kidney
vit D function
inc intestinal absorption of Ca2+ and Po43-
inc bone mineralization at low levels
inc bone resoprtion at higher levels
vit D regulation
inc PTH, dec Ca2+. dec PO43- > inc 1,25-(OH)2D3 production
1,25-(OH)2D3 feedback inhibts its own production
inc PTH > inc Ca2+ reabsorption and dec PO43- reabsorption in kidney
vit D def
rickets in children (deformity, genu varum bowlegs)
osteomalacia in adults(bone pain and muscle weakness)
hypocalcemic tetany
vit D def causes
malabsorption
dec sun exposure
poor diet
CKD
advanced liver disease
vit D excess
hypercalcemia
hypercalciruia
loss of apetite
stupor
seen in granulmatous disease
vit E name
tocopherol, tocotrienol
vit E def
hemolytic anemia
acanthocytosis
muscle weakness
demyelination of posterior columns (dec position and vibration sensation) and spinocerebellar tract (ataxia)
neuro presentation similar to B12, labs different
vit E excess
risk of enterocolitis in infants
alter vit K metabolism, inc anticoagulant effect of warfarin
vit K names
phytomenadione, phylloquinone, phytonadione, menaquinone
vit K function
reduced form is a cofactor for y-carboxylation of glutamic acid residues on various proteins required for blood clotting (clotting factors II, VII, IX, C and proteins C and S)
synthesized by intestinal flora
vit K def
neonatal hemorrhage with inc PT and inc a PTT but normal bleeding time
can occur after prolonged use of broad spectrum antibiotics
types of collagen
Be (So Totally) Cool, Read Books
type I (90%) - Bone, Skin, Tendon
type II - cartilage
type III - Reticulin (skin, BVs, uterus)
type IV - Basement membrane (basal lamina)
steps of collagen synthesis and processing
synthesis
hydroxylation
glycosylation
exocytosis
proteolytic processing
cross-linking
collagen synthesis
translation of collagen a chains (preprocollagen) - usually Gly-X-Y (proline or lysine).
glycine content best reflects collagen synthesis since it makes up 1/3
collagen hydroxylation
hydroxylation of specific proline and lysine residues; requires vit C (def = scurvy)
collagen glycosylation
glycosylation of pro-a-chain hydroxylysine residues and formation of pro-collagen via hydrogen and disulfide bonds (triple helix of 3 collagen alpha chains)
problems forming triple helix = osteogenesis imperfecta
collagen exocytosis
exocytosis of procollagen into extracellular space
collagen exocytosis
exocytosis of procollagen into extracellular space
collagen proteolytic processing
cleavage of disulfide rich terminal regions of procollagen > insoluble tropocollagen
problems with cleavage > ehlers danlos syndrome
collagen cross-linking
reinforcement of many staggered tropocollagen molecules by covalent lysine-hydroxylysine cross linkage (stabilized by copper containing lysyl oxidase) to make collagen fibrils.
problems with crosslinking = EDS, menkes syndrome
Osteogenesis imperfecta
Genetic “brittle bone disease” caused by gene defects, usually COL1A1 and COL1A2
Most commonly autosomal dominant with dec of type I collagen
BITE
Bones (multiple fractures)
I (eye, blue sclerae)
Teeth (dental imperfections)
Ear (hearing loss)
