Exam 1 Flashcards
What are the classes of functional, non-protein coding sequences
Promotor and enhancer regions (binding sight for TF)
Binding sights that maintain higher order chromatin structures
Regulatory RNAs (micro and long non-coding RNA)
Mobile genetic elements (transposons)
Telomeres and centromeres
What is the difference between euchromatin and heterochromatin
Euchromatin is transcriptively active
Heterochromatin is densely packed
What regulates chromosome separation at metaphase
Kinechtocore complex
Is there a greater or less GC content in bands
Less
What are the two most common forms of DNA variation in the human genome
Single nucleotide polymorphisms and copy number variations
What are SNPs
Variants at single nucleotide positions; almost always biallelic
What is linkage disequilibrium
If you have a neutral SNP but subsequently have a disease-associated gene as a result of physical proximity, the sNP and genetic factor are said to be in linkage disequilibrium
What is the difference between CNV and SNPs
CNVs can be biallelic but can also have complex rearrangements of genomic material with multiple alleles; CNVs also are involved in a greater percentage of coding sequences *indicates involvement in phenotypic diversity
What do chromatin remodeling complexes do
Reposition nucleosomes on DNA, exposing or obscuring gene regulatory elements
What do chromatin writer complexes do
Initiate covalent modifications of histones
Describe histone methylation
Lysine and arginines can be methylated by writer enzymes; can be associated with transcriptional activity or repression based on which histone residue is marked
Describe histone aceytlation
Lysine residues are acetylated by histone acetyl transferase, which opens chromatin ; reversed by deacetylation
Describe histone phosphorylation
Serine residues phosphorylated and depending on the residue, will either open or condense chromatin
Describe DNA methylation
results in transcriptional silencing; regulated by methyltransferases, demethylating enzymes and methylated DNA binding proteins
How many nucleotides are long no coding rNAs
> 200
What is the function of micro RNAs
Modulate the translation of target mRNAs into their proteins; *impt for posttranscriptional gene regulation
What is DICER important for?
Processing miRNAs after transcription; generates mature single-stranded miRNA associated with a multiprotein aggregate called RNA-induced silencing complex
What is the function of rNA-induced silencing complex (RISC)
When the miRNA binds to its corresponding base pairs on target mRNA, it directs the RISC to either induce mRNA cleavage or repress its translation
What is a seed sequence
All mRNAs have this sequence in their 3’ untranslated region (UTR) that determines the specificity of the miRNA binding and gene silencing
What are small interfering RNAs
They serve as substrates for DICER and interact with RISC similarly to miRNAs; used in lab to determine gene function and developing as therapeutic agents for oncogenes
What is XIST
An example of long noncoding RNA; transcribed from X chromosome and then provides repressive cloak over X chromosome and silences gen
Describe how miRNAs are made
Transcribed to a primary RNA which is processed in the nucleus to make pre-miRNA (ssRNA with secondary hairpin loop that form stretches of dsrNA); pre-mRNA exported out of nucleus and DICER trims it in cytoplasm to generate mature ds miRNAs; miRNA then unwinds and the single strands are incorporated into RISC
What are the roles of long noncoding RNA
Facilitate TF binding and promote gene activation
Bind TF and prevent gene transcription
Histone and DNA modification can be directed by binding of them
Can stabilize secondary or tertiary structures that influence chromatin structure
What are the functions that all differentiated cells must perform
Protection from environment, nutrient acquisition, communication, movement, renewal of senescent molecules, molecule catabolism, energy generation
What is the importance of isolating cellular functions
If there are degredative or hazardous enzymes, can keep in certain organelles without risking damage to other cellular machinery; also allows for unique IC environments that will allow maximum functionality of certain enzymes
Where are proteins that are destine for the plasma membrane or points beyond made
RER and modified in Golgi
Where are proteins intended for the cytosol made
Free ribosomes
Where are SERs abundant
Gonads and liver; used for steroid hormone and lipoprotein synthesis as well as modification of hydrophobic compounds into water soluble compounds for export (ie Metabolism of drugs)
What do peroxisomes do
Breakdown fatty acids, generating hydrogen peroxide
What is the cytoskeleton important for
Determining polarity of the cell; important in epithelium to determine apical and basal part of cell
What is the purpose of phosphatidylinositol on the inner cell membrane
Can be phosphorylated and serve as an electrostatic scaffold for intracellular proteins; or polyphosphoinositides can be hydrolyzes by phospholipase C to generate second messengers
What does phosphatidylserine do
On the inner membrane where it confers a negative charge involved in electrostatic protein interactions; when it flips to extra cellular surface (occurs in cells undergoing apoptosis), it signals phagocytes to eat the cell; *in platelets is a cofactor for blood clotting
Where are glycolipids and sphingomyelin normally expressed
On extracellular surface; glycolipids (especially ones with terminal sialac acids that confer negative charge) are impt for cell-cell/matrix interactions (including inflammatory cell recruitment and sperm-egg interactions)
What do integral membrane proteins contain on their cytoplasmic side?
Positively charged amino acids; anchors the protein to the negatively charged hydrophilic heads of the phospholipids
What does glycosylphosphatidylinositol do?
Anchors protein on the extracellular surface
Which two proteins are found mostly extracellularlly
Phosphatidylcholine and sphingomyelin
Which two proteins are mostly found on the inner membrane
Phosphatidylethanolamine and serine
Glycolipids are only found on which surface
Outer; contribute to glycocalyx
What do channel proteins create
Hydrophilic pores
What kind of transporter is multidrug resistant protein
ATPase; pumps polar compounds out of cells * cancer cells resistant to treatment
Loss in the ability to generate energy in a cell leads to what?
Osmotic swelling
What are caveolae
Invaginations of cell membrane that participate in endocytosis of small molecules
What is transcytosis
Movement of material from apical to basal side of cell; plays a role in increased vascular permeability during healing wounds and tumors
What are caveolae associated with
GPI linked molecules, cAMP binding proteins, SRC family kinases, and folate receptor
What are the main functions caveolae-mediated endocytosis are involved in
Regulate signaling and adhesion by internalizing receptors and integrins
Which two cellular processes begin at the clathrin coated pit
Pinocytosis and receptor mediated endocytosis
What are two examples of molecules that use receptor mediated endocytosis
Transferrin and LDL; in the environment of the lysosomes, they release iron and cholesterol and are then recycled back to membrane
What are actin microfilaments
Form from G-actin -> noncovalently polymerize into F-actin that intertwined to form ds helices that forms a polarity
What are intermediate filaments useful for
Can be used to determine origins for poorly differentiated tumors;
Lamin: nuclear lamina of all cells (mutations involved in MD and premature aging - progeria)
Vimentin: mesenchymal cells (fibroblasts, endothelium)
Desmin: m cells
Neurofilaments: axons
Glial fibrillary acidic protein: glial cells
CYtokeratins: distinct varieties (acidic type I and neutral/basic type II)
What is the overall function of intermediate filaments
Do not actively reorganize; are important for allowing cells to bear mechanical stress; major structural proteins of skin and hair
What are microtubules
Diverse of alpha and beta tubules; defined polarity; - side embedded in microtubule organizing center near the nucleus where it is associated with centrioles; + end elongates or recedes in response to stimuli by adding or subtracting tubulin; act as connecting cables for proteins that use ATP to move vesicles or other molecules
What are the two kinds of microtubues
Kinesins: anterograde - to + transport
Dyneins: retrograde + to - transport
Also participate in sister chromatid separation during mitosis; have also adapted to form cilia in sperm and bronchial epithelium
What are tight junctions made up of
Occludin, claudin, zonulin, and catenin
What are the two types of desmosomes
Between cells: spot desmosomes or macula adherens
Between cell and ECM: Hemidesmosomes
What proteins are involved in desmosomal junctions
Cadherins; in belt desmosomes E cadherin - associated with actin (influence shape and motility) in spot desmosomes Demogleins or desmocollins associated with intracellular intermediate filaments; in hemidesmosomes integrin
What are focal adhesion complexes
Localized at hemidesmosomes; include proteins that can generate intracellular signals when cells are subjected to increased shear stress (ie: endothelium or cardiac myocytes)
What forms gap junctions
Connexons; important in cardiac tissue (permits uniform contraction); permeability of junctions is decreased by low intracellular pH or increased calcium
What is the function of chaperon molecules
Keep proteins in the ER until folding is complete
What is the ER stress response
If you have an overload of misfolded proteins t hat need to be degraded, ER cant handle it, which triggers apoptosis
The Golgi apparatus modified proteins from ______ conformation to ______
Cis; trans
What is the difference in function between the cis Golgi and the trans golgi
Cis can recycle proteins back to ER
Trans sends them to other organelle or to be released
Which cells have abundant golgi
Goblet, bronchial epithelium, plasma
Where are lysosomal enzymes made
ER; then tagged with a mannose-6-phosphate residue in the golgi; allows it to be delivered to lysosomes
What is heterophagy
Lysosomes fuse with endosomes or phagosomes to degrade internal contents; end products are either released into cytosol or discharged into ECM via exocytosis
What is autophagy
Senescent organelles or denatured proteins are targeted for lysosomes driven degradation by encicircling them with double membrane derived from the ER and marked by LC3 proteins; can be activated by nutrient depletion or intracellular infections
Describe the process of proteasome degradation
Cytosolic proteins are tagged with ubiquitin as a result of extrinsic mechanical or chemical stress via E 1,2,3 ubiquitin ligases
Mitochondrial disorders can be ________
Autosomal, X linked or maternally inherited
What is the intermembrane space of the mitochondria
Site of ATP synthesis
What does the oxidation of sugar drive in the mitochondria
H+ pump that drive H+ out of the matrix into the intermembrane space; as the H+ flow back down their gradient, the energy released is used to make ATP
What is the Warburg effect
Since pure oxidative phosphorylation doesn’t leave any carbon to make lipid or proteins, rapidly growing cells upregulate their glucose and glutamine uptake and decrease their ATP production/glucose; intermediates of TCA cycle are used to make proteins
Describe the process of necrosis
External cellular injury causes formation of mitochondrial transition pores, allowing dissipation of the proton gradient and therefore no ATP is generated and cell dies
How do mitochondria take part in apoptosis
Intrinsic pathway; if mitochondria damaged or cell cannot make survival proteins, mitochondria become leaky and let out cytochrome c -> activates caspases
What is unique about NO as a ligand
It can diffuse into adjacent cells
What molecules bind to RTK
Insulin, epidermal growth factor, and platelet derived growth factor
What is the notch receptor
Recognizes ligand and is cleaved -> enters nucleus and affects transcription
What does activation of the wnt/frizzled pathway lead to
Release of beta catenin which acts as a TF; *LDL related receptors act this way; beta catenin usually ubiquinated - activation of this pathway recruits disheveled protein to disrupt the degredation complex
Explain the RTK pathway
Autophosphorylates which causes bridging protein to put GTP on RAS and activate it -> activates RAF -> phosphorylates MAPK -> phosphorylates transcription factors, generating responses; RAS can also activate PI3K -> Akt -> mTOR
What is the function of adaptor proteins
Modulates cell signaling
What must a TF contain in order to induce transcription
Protein:protein interaction domain that recruit histone modifying agents, chromatin remodeling complexes, and RNA polymerase
Besides proliferation and growth, what else do growth factors initiate
Migration, differentiation, and synthetic capacity
What are epidermal growth factor and transforming growth factor produced by
Macrophages and epithelial cells
Mutations of EGFR1 cause what
Cancers of lung, head and neck, breast and brain
What is overexpresion of the ERBB2 linked to
Breast cancer (HER2)
What is the function of hepatocyte growth factor
Acts as a morphogen embryologically (influences pattern of tissue differentiation), promotes cell migration (scatter factor), and enhances hepatocyte survival
What is HGF produced by
Fibroblasts, non-hepatocyte liver cells, endothelium, and mesenchymal cells
How is HGF activated
Synthesized as pro-HGF, activated by serine professes at site of injury; MET is receptor (RTK)
What is a mutation or overexpression of MET associated with
Renal and thyroid papillary carcinomas
What are the isoforms of platelet derived growth factor
AA, AB, BB: constitutively active
CC and DD: activated by proteolytic cleavage
What produces PDGF
Platelets, macrophages, endothelium, smooth m, tumors
What are the receptors for PDGF
PDGFR alpha and beta (RTK); induce fibroblast, endothelial and smooth m proliferation; *chemotactic
What are the vascular endothelial growth factors
A, B, C, D and placental growth factor
What is VEGF-A involved in
Angiogenesis after injury and in tumors
What are VEGF B and PIGF involved in
Embryonic vessel development
What are VEGF C and D involved in
Angiogenesis and lymphatic development
Where are VEGFs expressed the most
In epithelium cells next to fenestrated epithelium (podocytes in kidney, pigmented epithelium in retina, and choroid plexus in brain)
What is the most important inducer of VEGF production
Hypoxia via pathways that involve hypoxia inducible factor; VEGF causes vascular dilation and increased vascular permeability; also induced by PDGF and TGF alpha
What do VEGFs bind to
RTKs (VEGFR 1 and 2); 2 is found mostly on endothelium and is most important for angiogenesis
What are abs to VEGF used to treat
Tumors especially in renal and colon (decreases vascular supply for growth); also used to treat we AMD
What does increased levels of soluble versions of VEGF1 in pregnant women cause
Preeclampsia
What do released fibroblast growth factors associate with
Heparan sulfate in ECM; released by proteolytic
What do FGFs bind to
FGGR 1-4 (RTK); contribute to wound healing, hematopoiesis, and development; *basic FGF can also do angiogenesis
What other proteins are in the same family as TGFbeta
BMPs, activins, inhibits, mullerian inhibiting substance
Which isoform of TGFbeta is the most widespread
1
What are the TGFbeta receptors
Serine/threonine kinases; induce phosphorylation of smads which form heterodimers with smad4, allowing nuclear translocation and association with DNAbinding proteins to activate or inhibit transcription
What is a pleiotropic agent
An agent that has multiple affects depending on the tissue; TGFbeta is an example
What are the functions of TGFbeta
Stimulates production of collagen, fibronectin, and proteoglycans; inhibits collagen degredation by decreasing matrix metalloproteinase (MMP) activity and increasing activity of tissue inhibitors of proteinases (TIMPs); drives fibrosis in situation of chronic inflammation; anti inflammatory cytokines by inbhiting lymphocyte proliferation
What are the two forms of ECM
Interstitial matrix: space between cells in connective tissue and btw parenchyma epithelium and vascular and smooth m; synthesized. By mesenchymal cells; made up of fibronectin, elastin, collagen, proteoglycans, hyaluronate
Basement membrane: organized interstitial matrix around epithelial cells, endothelial cells and smooth m cells; made up of nonfibrillar type IV collagen and laminitis
What are the components of the ECM
Fibrous structural proteins: elastin and collagen
Water-hydrated gels: proteoglycans and hyaluronan (permit compressive resistance and lubrication)
Adhesive glycoproteins: connect ECM elements to one another and cells
What are fibrillar collagens
Form linear fibrils stabilized by hydrogen bonds; form connective tissue; tensile strength derived from lateral cross linking formed by covalent bonds vis the activity of lysyl oxidase *dependent on vitamin C (children with ascorbate deficiency have skeletal deformities and bleed easily)
What do nonfibril collagens do
Form basement membranes, help regulate collagen fibril diameters or collagen-collagen interactions via fibril-associated collagen with interrupted triple helices (FACITS - type IX in cartilage), or provide anchoring fibrils to basement membrane beneath strat squamous epithelium (Type VII)
Where is elastin most important
Valves, BV, uterus, skin, ligaments
What are elastin fibers made up of
Elastin core with associated mesh work of fibrillin; fibrilllin defect can cause skeletal abnormalities and weakened aortic walls (Marfan)
What do proteoglycans consist of
Glycosaminoglycans (keratan sulfate and chondroitin sulfate) attached to a core protein; these are linked to a hyaluronic acid polymer (hyaluronan)
Do collagen fibers have elasticity
No
Does lysyl oxidase also have an effect on elastin
Yes; cross links them as well, but have hydrophobic segments that form a blob during rest, when stretched, these segments separate but the cross linking keeps the strand in tact
How do proteoglycans form gel like matrix
The negative charge of the sulfated sugars recruit sodium and water
How is bFGF regulated by ECM and cellular proteoglycans
Syndecan has side chains that can bind bFGF that has been released from damaged ECM; it also has a cytoplasmic tail that interacts with the actin cytoskeleton
What are adhesive glycoproteins
Fibronectin and laminin
What are adhesion receptors
Integrins, immunoglobulins, cadherins, and selectins
What does fibronectin do
Provides scaffolding for subsequent ECM deposition, angiogenesis, and reepithelialization
What does laminin do
Connects cells to ECM components such as type IV collagen and heparan sulfate; also modulates cell proliferation, differentiation, and motility
What do integrins do
Allow cells to attach to ECM components such as fibronectin and laminin; on surface of leukocytes essential in mediation firm adhesion at sites of inflammation; attach via tripeptides arginine glycine aspartic acid motif
What are the phases of the cell cycle
G1: presynthetic growth
S: DNA synthesis
G2: premitotic growth
M: mitosis
What is cell cycle progression driven by
Cyclins and cyclin dependent kinases
What happens as the CDK completes its round of phosphorylation
The associated cyclin is degraded and CDK activity abates
What do CDK inhibitors do
Enforce the cell cycle checkpoints by modulating CDK-cyclin complex activity
Which cells do not proliferate
Neurons and cardiac cells
Which proteins selectively effect cyclin CDK4 and CDK6
P15, p16, p18, and p19
Which CDKs regulate the G1 to S transition?
D-CDK 4, 6, and E-CDK2; they do so by phosphorylating the Rb protein
Which cyclins are activated in the S phase
A-CDK2 and ACDK1
Which CDK is essential for the G2 to M transition
B-CDK1
Where are adult stem cells found
In niches; factors and other cells here keep the stem cells quiescent until there is a need for expansion and differentiation
What can be administered to cause release of hemopoeitic stem cells from their bone marrow niches
CSF
What are mesenchymal stem. Cells
Multipotent cells that can give rise to bone, cartilage, muscle and fat; can generate local immunosuppressive environment; thought to be involved in tissue regeneration
What is CRISPRs
Guide RNAs that are used in conjunction with Cas9 to selectively alter or correct DNA sequences
Where are stem cell niches in various tissues
Skin: hair follicles Liver: Hering canals (connect bile ductules to hepatocytes) SI: base of crypt above paneth cells Cornea: limbus Brain: subventricular zone and dentate
What are the adaptive responses
Hypertrophy, atrophy, metaplasia, hyperplasia
What does nutrient deprivation trigger
Autophagy
What is often deposited at sites of cell death
Calcium; pathological calcification
What causes physiologic hypertrophy
Increased workload or hormone-induced (pregnancy)
Describe the pathogenesis of cardiac hypertrophy
Mechanical sensors induce production of growth factors (TGFbeta, IGF1 and fibroblast growth factor) and vasoactive agents; these activate PI3K/ AKT pathway -> activates GATA4, and myocyte enhancer factor 2 (Both TF) which increases production of m proteins responsible for hypertrophy
Switch of contractile proteins during hypertrophy does what?
Ie: in m hypertrophy, alpha myosin heavy chain is replaced by beta, which is slower, but more energetically economical; also evidenced in cardiac m (example: ANP is expressed in both atria and ventricles early in life, but downregulated; cardiac hypertrophy associated with increased ANP in order to reduce hemodynamic load)
What is an example of hormonal hyperplasia
Glandular breast tissue during puberty and during pregnancy
What are examples of pathological hyperplasia
Endometrial, BPH, can be in response to a virus such as HPV
What are examples of physiologic atrophy
Thryoglossal duct, notochord, decrease in size of uterus after birth
What is senile atrophy
Atrophy of the brain caused by decreased perfusion
What is marasmus
Malnutrition
How do chronic inflammatory diseases cause atrophy
Overproduction of TNF decreases appetite and depletes lipids
How can loss of endocrine function lead to atrophy
Some m require hormonal stimulation for normal metabolism (ie: uterus and breast)
How does pressure cause atrophy
Ie: a tumor pressing on a muscle -> decreases blood supply
What cellular changes occur in atrophic mm
Decrease cell size and organelles to reduce metabolic needs, have fewer mitochondria, microfilaments, and RER to achieve new equilibrium
What are lipofuscin granules
Residual bodies left by autophagic vacuoles that resist digestion; cause brown discoloration to the tissue
What is the most common metaplasia
Columnar to squamous (ie: smokers)
What kind of deficiency can lead to induction of squamous metaplasia in the respiratory epithelium
Vitamin A
Where does squamous to columnar metaplasia occur
Barrett esophagus
What is connective tissue metaplasia
Formation of cartilage, bone, or adipose tissue in tissues that normally don’t contain these elements (ie: bone in muscle - myositis ossificans; occurs after intramuscular hemorrhage); less of an adaptive response, more of response to cell injury
What is the mechanism of metaplasia
Reprogramming of stem cells; precursor cells differentiate along a new pathway
A deficiency in what vitamin can cause metaplasia
Vitamin A; also with excess *regulates gene transcription which influences differentiation of stem cells
What are the hallmarks of reversible cell injury
Cell swelling caused by changes in ion concentration and ATP depletion because of reduced oxidative phosphorylation
Is necrosis always pathological
Yes; apoptosis isn’t always
Compare necrosis to apoptosis
Necrosis: swelling, no nucleus, disrupted plasma membrane, enzymatic digestion of cellular contents -> leak out of cell; produced adjacent inflammation, pathological
Apoptosis: cell shrinkage, nucleus is fragmented, intact plasma membrane (but structure different - orientation of lipids), intact cellular contents, no adjacent inflammation, physiologic usually
What features of reversible injury can be seen under the microscope
Cell swelling and fatty change; plasma membrane alterations (blending, blunting, loss of microvilli), mitochondrial changes (amorphous densities), dilation of the ER; intracytoplasmic myelin figures
What is hydropic change or vacuolar degeneration
Under microscope, cell swelling can be viewed as small clear vacuoles which are distended and pinched off segments of the ER
Where are the enzymes that digest the necrotic cell derived from
Lysosomes of the dying cell as well as from the leukocytes that come in as part of the inflammatory reaction
Why do necrotic cells show increased eosinophilia
Because of the loss of cytoplasmic RNA which binds the blue dye and because of the denatured cytoplasmic proteins which binds the red dye
What are myelin figures
Phospholipid masses derived from the damaged cell membranes; they are phagocytosis or further degraded into fatty acids; calcification of these fatty acids can result in production of calcium soaps
Describe the nuclear changes of a necrotic cell
One of three patterns:
Karyolysis: basophils of chromatin fades because of loss of DNA
Pyknosis (also seen in apoptosis): nuclear shrinkage and increased basophilia; chromatin condenses into a mass
Karyorrhexis: pyknotic nucleus undergoes fragmentation
What is coagulative necrosis
Architecture of the dead tissue preserved for a span of a few days; firm texture; denatures enzymes so blocks proteolytic of the dead cells so they persist until leukocytes break them down; localized area is called infarct *ischemia can cause this to all tissues except the brain
What is liquefactive necrosis
Characterized by digestion of the dead cells; transforms tissue into liquid mass; seen in focal bacterial or fungal infections; frequently creamy yellow because of dead leukocytes (pus); *seen with hypoxic death of cells within the CNS
What is gangrenous necrosis
Not a specific pattern of cell death; involves coagualative necrosis and if liquefactive necrosis is also involved can give rise to wet gangrene
What is caseous necrosis
Structureless collection of fragmented or loses cells and granular Debra with distinct inflammatory border; *granuloma
What is fat necrosis
Focal areas of fat destruction usually caused by release of active pancreatic lipases into peritoneal cavity (acute pancreatitis) fatty acids that are produced from this breakdown combine with calcium to produce chalky white areas (saponification)
What is fibrinoid necrosis
Usually seen in immune reactions involving blood vessels; occurs when ab-ag complex deposited on walls of BV; results in bright pink appearance on slides
What effects does mitochondrial damage of
Decreases ATP and increases ROS (causes damage to lipids, proteins and DNA)
What effect does the entry of Ca2+ have in cell death
Increases the permeability of mitochondria by opening the pore and thus decreases ATP generation, and activates multiple cellular enzymes (phospholipases - membrane damage; processes, endonucleases - DNA fragmentation, and ATPases), also directly activate caspases
What are the effects of decreased ATP?
Decreases Na/K pump so cell swells, increase in anaerobic glycolysis (AMP stimulates PFK and phosphorylase)-> decreases glycogen, increases lactic acid (which decreases pH and causes clumping of nuclear chromatin), detachment of ribosomes which causes decreased protein synthesis
What is cyclophilin D
Part of the mitochondrial permeability transition pore (targeted by the immunosuppressive drug cyclosporine)
What is oxidative stress
When production of free radicals outpaces the body’s ability to eliminate them
How are free radicals produced
Reduction-oxidation reactions, absorption of radiant energy, activated leukocytes during inflammation reactions (uses NADPH oxidase), enzymatic metabolism of drugs, transition metals (Fenton reaction), NO can also act as a free radical
What are examples of antioxidants
Vitamins E and A, ascorbic acid and glutathione
What are the enzymes that breakdown H2O2 and superoxide anion
Catalase (peroxisomes)
Superoxidase dismutases
Glutathione peroxidase *Ratio of oxidized glutathione to reduced glutathione is a reflection of oxidative state of the cell
What is lipid peroxidation in membranes
In the presence of O2, free radicals can attack the double bonds of the unsaturated fA of the membrane (specifically OH); this yields peroxides which are also unstable and reactive -> propagation
What are examples of oxidative modification of proteins
Free radicals promote oxidation of amino acid side chains, formation of covalent protein-protein cross links (Disulfide bonds), and oxidation of protein backbone; can damage active sites, disrupt conformation of protein, and enhance degredation of misfolded proteins
What can free radicals do to DNA
Breaks in DNA, cross linking; linked to cell aging and malignant transformation
