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101 Cards in this Set
- Front
- Back
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Different Filaments in Cells
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Microfilaments (7nm)
Intermediate Filaments (10 nm) Microtubules (25nm, hollow core) Thick Filaments (15nm) |
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Seeing Microfilaments
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Use:
- EM - Antibodies + immunofluorescence - Labelled Phalloidin/Phallacidin - Actin tagged with Green Fluorescent Protein (GFP) |
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Phalloidin/Phallacidin
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Toxins from death cap mushroom, stabilize actin so that you can see it. Poisonous...
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Cell Migration Elements
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- Cell extension (actin polymerization)
- Cell adhesion (integrins interact with ECM protein like fibronectin) - Cell contraction (generation of force by myosin interacting with actin) |
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Actin General Features
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Globular G protein (G-actin), polymerizes into helical filaments (F-actin)
Polarized (arrowhead model). Barbed end is preferred for actin addition, pointed end is preferred for dissociation of actin. |
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Actin Polymerization/Regulation
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In nonmuscle, actin is mostly unpolarized. Maintained in G-actin state by protein that binds and stabilizes (can't polymerize)
Specific signals (Arp2/3, for example) trigger polymerization needed for plasma membrane extension (branching). |
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Arp2/3
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Protein that binds to sides of actin filament and nucleates new filaments that branch off. Branching of actin pushes membrane forward. Combine with membrane growth in front and shrinking in back to cause cell movement!
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Cytochalasin D
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Protein that inhibits actin polymerization. Blocks cell migration, phagocytosis, mitosis.
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Phalloidin/Phallacidin
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Protein that block depolymerization. Prevents cellular movement. Both adding and removing actin is key to movement!
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Crosslinking/Remodelling crosslinked fibers
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Polymerizes actin crossed with other protein to form networks/bundles. EX: Filamin, flexible dimer.
Actin and filamin crosslinked creates rigid cell cortex structure. To move cell, need to remodel cell cortex, destroy crosslinked filaments. Use gelsolin (Ca2+ activated, severs actin filaments) |
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Actin and ATP/ADP
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G-actin can bind ATP and ADP.
Preferred form is ATP, after polymerization goes to ADP. Aged filament has mostly ADP. Arp2/3 prefers ATP. Depolymerizing protein cofilin prefers ADP. |
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Muscle Contraction
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Results from myosin II (most common type) interacting with actin.
Muscle contracts: filaments slide with respect to each other (thin over thick), Z lines move closer together. |
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Skeletal Muscle
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AKA Striated muscle.
Composed of bundles of muscle fibers. Multinucleated from fusion of myoblasts. Each fiber made of myofibrils. Each myofibril contains sarcomeres (give striations). Each sarcomere has thick filament (myosin) and thin filament (actin). Thin filaments are similar to microfilaments. They attach to Z lines that border sarcomere. |
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Myosin II
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Large protein, 2 heavy chains and 2 light chains. Head domain is known as heavy meromyosin (HMM). Binds to actin and has ATPase activated by actin.
HMM has two sufragments, #1 binds actin/has ATPase activity. |
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Other Myosins
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Many types, though II is most common. Mutations can lead to blindness/deafness.
Usher syndrome is mutation of myosin VIIA, makes people blind and deaf. |
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Sarcomere Organization
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Alpha-actinin binds filaments to Z lines. Tropomyosin and troponin are along actin filament and regulate interaction with myosin.
Calcium released by sarcoplasmic reticulum binds troponin, causes shape shift. Lets myosin (S1) bind to actin and generate force. Release myosin head by hydrolyzing ATP to ADP. |
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Crossbridge Cycle (in muscles, for example)
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1) Attached: myosin attached without ATP to actin. Rigor position, like in rigor mortis.
2) Released: ATP binds to myosin, conformation change detaches it from actin. 3) ATP hydrolysis (leaves ADP and Pi bound to myosin) binds myosin to next actin 4) Force generation: interaction of myosin with actin dissociates Pi and ADP, providing force to move filament and restore first step conditions. |
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Regulation of Actin in non-Muscle
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Regulation by G protein.
Rho, Rac, Cdc42 are all part of Ras family, active when GTP is bound, inactive when GDP is bound. They have GTPase activity, stimulate stress fiber and focal adhesion creation. |
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Rac
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Rac stimulates actin polymerization and extension of membrane ruffles and lamellipodia (sheet like extensions).
Activated by Arp2/3 |
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Cdc42
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Stimulates actin polymerization in non-muscle, extension of finger like protrusions, filopodia.
Activated by Arp2/3. |
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Wiscott-Aldrich Syndrome
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Cdc42 activated protein is defective (WASP). There are two genes for this protein, one expressed everywhere and one in platelets/leukocytes. WAS has abnormal platelets and inhibited migration (Cdc42 is inhibited).
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MLCK
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Myosin light chain kinase, activates myosin outside the muscle (as opposed to troponin). Also Ca dependent.
When Ca present, (P)s myosin light chain, stimulating activity with actin. Lets myosin assemble into small bipolar filaments. |
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Rho
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Elevates (P) addition to myosin light chain.
Activate ROCK (Rho Kinase) which directly (P)s light chain. ROCK also (P)s phosphatase of light chain. Acts independently of calcium. |
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States of Actin in nonmuscle
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1) G-acitn
2) Networks/gels 3) Actin bundles |
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Actin Bundles in Nonmuscle
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- Contractile ring in mitosis cytokinesis.
-Microvili, stereocili of hair cells in hearing - Stress fibers, most common bundles, anchored in focal adhesion where cells adhere to ECM along with integrins. Stress fibers also involved in healing wounds (don't stretch but contain myosin II). |
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Transformed Cells (oncogenically modified)
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Lack stress fibers/focal adhesions. This usually only happens during mitosis.
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Attachment of Actin filaments to membranes
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Focal adhesion is one example.
RBCs is another: membrane skeleton. Short actin filaments bind to large protein, spectrin. This in turn binds to ankyrin, which binds to integral membrane band 3. Diseases affecting these prots make weird RBCs. Elliptocytosis (hereditary) has weird RBCs, defective spectrin. Hereditary spherocytosis has defective ankyrin, leads to spheres for RBCs. Fragile, rapidly destroyed. Severe anemia results. Spectrin also in other cells. Same family includes alpha actinin and dystrophin. Dystrophin involved in linking actin filaments to plasma membranes. Mutated in DMD, leading to damage and death of muscle cells, paralysis and death. X linked recessive. |
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Microtubules
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Thicker than intermediate filaments. Parts of cilia and flagella. Arranged in a 9+2 configuration, with 9 outer doublet microtubules and one inner pair of single microtubules.
Cilia and flagella generate cell locomotion (sperm) or movement of fluid over epithelial cell surfaced (ova, bronchi). |
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Axoneme composition
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Array that makes up whole 9+2 unit in cili/flagella.
Each outer doublet has A tubule (13 protofilaments) and B tubule (10 protofilaments). Each protofilament is an alpha/beta tubulin heterodimer. Extending from each A tubule are 2 arms that interact with neighboring (not attached) B tubule. These arms are made of dynein. |
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Dynein
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Makes up arms from A tubule in axoneme.
It's an ATPase activated by MTs. Essential for suing cilia and flagella. People without dynein (Kartagener's syndrome) are infertile, high bronchial disease. About half of them have reversed organs. |
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Basal Body
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Axoneme on each cilium/flagellum grows out of basal body which has 9 TRIPLET microtubules.
Basal bodies are like centrioles (also have 9 triplet microtubules). |
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Centrioles
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Have 9 triplet MTs. Found as paired cylinders at 90 degree angles. Stay close to nucleus, inside the centrosome (aka MTOC microtubule organizing center).
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Centrosome/Centriole
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Centrosome is source of all cytoplasmic MTs. Centrioles are duplicated during cell cycle (get four) and form the poles of the mitotic spindle.
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Cilia as detectors
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Cilia can detect signals.
Photoreceptors on modified cilia in rods and cones. Olfactory receptors linked to cilia on sensory neurons. |
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Primary Cilium
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Quiescent cells develop a single primary cilium that grows from the centriole. Has mechanotransduction role.
Defects lead to disease like polycystic kidney disease. Results from mutation in signaling protein linked to cilia. Normally flow of urine in the kidney bends cilia, stimulating the pathway. In PKCD, lack of flow leads to straight cilia, activating proliferation pathway. Uncontrolled growth, cysts. To go through cell cycle, need to disassemble primary cilium so centrioles can duplicate. |
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Cytoplasmic Microtubules
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Single MTs are important for cytoskeleton element. They are also key structures in mitotic spindle and in separating chromosomes.
Drugs preventing mitosis promote depolymerization of MTs (colchicines, colcemid, nocodazole, vinblastine). Taxol also blocks mitosis but by hyperstabilizing structure, not depolymerizing it. Show mitosis is dynamic. These drugs are chemotherapeutic. Are also anti-fungals. Blocking cells in mitosis is used in karyotyping, like in amniocentesis. Colchesine is the big one. |
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Microtubule Organization
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MT arrays come from centromeres. Run to cell boundaries.
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Dynamic Instability
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MTs from centromere are simultaneously polymerizing and depolymerizing. Allows for rapid remodeling, like building mitotis spindle.
MTs are polar, like actin. Ends not anchored to centromere are (+) end, favored for tubulin subunit addition (polymerization) (-) ends are anchored at the centrosome. |
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MTs in axons... and elsewhere
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Especially prominent. Establish the asymmetry of nerve cells. Are key in generating axoplasmic transport (motion of organelles down and up axon).
In general used for organelle transport. Also serve structural role, like in pillar cells of ear, where large arrays give them mechanical strength. |
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MT Polymerization
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Tubulin is most abundant protein in brain. Exists as alpha/beta heterodimers, polymerize to make 13 protofilaments with hollow core.
Microtubule Associated Protein (MAPs) promote polymerization. Some attach MTs to organelles, or other cytoskeletal elements (intermediate filaments). Addition/removal of tubulin units can happen at both ends, though (+) preferred for addition. Dynamic instability involved GTP bounds by tubulin. During poly, tubulin has GTP hydrolyzed at much slower rate than addition. Once turned into GDP, rate of depoly is dominant. GTP--> Growth (GTP cap) GDP-->Shortening. |
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Microtubule Motors
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Major function of MTs is movement (chromosomes, organelles).
Dyneins (cytoplasmic variety, similar to one in cilia/flagella). Activated by MT, ATPases that move organelles towards (-) (retrograde). Kinesins move organelles towards (+) end of the MTs (antiretrograde). |
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Mitotic Steps
Prophase |
P>PM>M>A>T>C
Chromatin condenses, can see chromosomes. Interphase microtubules disassemble and the mitotic spindle develops outside nucleus. The two poles (mitotic centers) of the spindle develop around the two centriole pairs (these duplicate before S phase). |
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Prometaphase
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Nuclear envelope breaks down. MTs from mitotic spindle associate with kinetochores (on centromeres of each chromosome).
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Metaphase
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Chromosomes align along metaphase plate. Under tension.
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Anaphase
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Move chromosomes to opposite poles. Kinetochore MTs shorten. Polar MTs elongate so poles are separated. TWO MOVEMENTS: chromatid separation and separation of the poles. Cyclin B rapidly degraded.
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Telophase
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Chromatids arrive at poles. Nuclear envelope forms around daughter chromatids.
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Cytokinesis
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Contractile ring of microfilaments forms perpendicular to the spindle. Actin and myosin constrict the plasma membrane forming the cleavage furrow. Cells “pinch off”. Sometimes a cytoplasmic bridge between the two, the midbody, remains for a while and contains the spindle MTs.
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Motor Action in Mitosis
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Many theories. Co-ordinated action of motors and poly/depolymerization. A dynein at the kinetochore move towards the mitotic pole, accompanied by depolymerization of the polar MTs.
There is also polymerization of polar MTs (driven by a kinesin)coupled with sliding as pole separation happens. |
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Intermediate Filament
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Four classes, all act as structural features (not motor)! Provide mechanical strength, resistance to tearing.
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Type 1 Filaments
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Tonofilaments, keratins, cytokeratins. Found in epithelia, most abundant protein of skin, hair, nails. They are in desmosomes, hemidesmosomes and provide tensile network that extends through the epithelium. Identifying overexpressed keratin lets you find type of tumor.
Desmosomes link intermediate filaments to cell to cell interactions. Hemidesmosomes link IF (intermediate filaments) to the ECM (via the basement membrane, contain integrins). |
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Keratin Defects
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Associated with skin/epithelium disease.
EBC (epidermolysis bullosa simples) associated with severe blistering, caused by keratin defects. |
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Type III Filaments
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Neurofilaments. Found in nerve cells. Amount is tied to diameter of axon. They are crosslinked with MTs and actin by large protein (plectin).
Disrupting these leads to nerve cell degradation. |
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Nuclear Envelope
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Perinuclear cistern derived from ER system makes inner and outer nuclear membrane
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Nuclear Pore Complex
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NPC:
found throughout the nuclear envelope and promotes exchange with the cytoplasm. Around 3000 of them per nucleus. EX: mRNA, tRNA, ribosomal subunits going out, or lamins, histones, polymerases coming in! Transport either by free diffusion or signal mediated. Less than 50kDa can diffuse, other compounds up to 25nm in diameter are transported using nuclear localization signal (NLS). Protein with NLS signal binds to NLS receptor, protein receptor complex transported through NPC. Process regulated by Ran (GTP binding protein of the Ras family). |
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Nuclear Lamina
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Made of 3 major protein, lamins A, B and C which are related to intermediate filament subunits. Form a skeleton that keeps the nuclear shape even after loss of nuclear membrane. Mitotic cells do not have an intact nuclear lamina. Disassembly linked to chromosome condensation, and done by (P)ing laminas.
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Laminopathies
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comes from mutations in lamin. Hutchinson-Gilford progeria syndrome is most common, from mutation in lamin A. Age quickly, get old age diseases before they’re 10 (senility, atherosclerosis).
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Heterochromatin
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Condensed form of chromatin, inactive in RNA synthesis
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Euchromatin
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Expanded chromatin, can be used for RNA synthesis. mRNA and tRNA are made on euchromatin, spliced and exported through nuclear pores.
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Nucleolus
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Round, granular-fibrilar structures associated with certain chromosomal sites containing nucleolar-organizing regions. They are needed for ribosome synthesis. The pre-rRNA (45S) is processed into:
- 28S in large subunit (60S) - 18S in small subunit (40S) |
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Common purines
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Adenine (6 aminopurine) (makes Adenosine)
Guanine (2amino6carbonylpurine) (makes guanosine) Hypoxanthine (6-carbonylpurine) (makes inosine) Xanthine(6,2bicarbonyl) (makes xanthosine) |
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Common pyrimidines
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Uracil (2,4 bicarbonyl pyrimidine)
Cytosine (2 carbonyl,4amino) Thymine (2,4 bicarbonyl, 5methyl) |
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Nucleoside
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Base + Sugar
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Nucleotide
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Base + Sugar + Phosphate
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De Novo Synthesis of Purines (first and regulated steps)
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First step is PRPP synthesis. Uses PRPP synthase.
Add PPi on ribose 5 phosphate (ATP goes to AMP). First commited step is regulated by PRPP amidotransferase. Make 5(P)ribosyl-1-amine by taking an amino group from glutamine. |
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Overall Steps, Synthesis of Purines
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Start with PRPP (from R5P).
1) Need two AAs from glutamine 2) Need ATP 3) Need THF 4) First make IMP, then convert to AMP, or to GMP via XMP. |
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Regulation
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For PRPP amidotransferases:
a) IMP, XMP, AMP, GMP (endproducts) inhibit b) PRPP stimulates For going from IMP to AMP from GMP: a) ATP needed to make GMP and GTP needed to make AMP b) AMP inhibits AMP synthesis, GMP inhibits GMP synthesis |
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Folic Acid Synthesis
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Folic acid is converted to tetrahydrofolic acid (THF) by dihydrofolate reductase. You reduce three bonds on the ring.
THF is needed to make dTMP and purine rings. Making dTMP actually consumes THF, while purine synthesis needs it as coenzyme. If you block DHF->THF, you kill dividing cells. (run out of THF in making more DNA, then can't make protein either since purines can't be made (mRNA). Regular (non-dividing cells) don't have a problem. Methotrexate does just this. |
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THF cycle details
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1) A, B and C are 1C derivatives of THF, all in equilibrium. Have different oxidation levels.
2) Ser, Gly, His and HCOOH (formic acid) are sources of carbon in making A/B/C 3) A, B and C are source of 2 carbons in purine rings, and of the methyl group in dTMP. |
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De Novo Pyrimidine Synthesis (Overall Pathway)
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1) Start with glutamate, ATP and CO2
2) Make carbamoyl phosphate (CP) from glutamate [ENZYME = CP SYNTHETASE ONE] 3) This is first commited step 4) Orotic acid is free base intermediate, convert to nucleotide by reacting with PRPP (makes OMP) 5) CTP is made by amination of UTP (need glutamine and ATP) 6) dTMP is made by methylation of dUMP by THF derivative. Converts THF back to DHF. |
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Regulation of Pyrimidine Synthesis
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1) In mammals, first commited step is glutamine->CP and is inhibited by UTP and promoted by PRPP
2) In bacteria, second enzyme (aspartate transcarbamoylase) is limiting. It is inhibited by CTP and promoted by ATP (endproduct/substrate). |
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Making deoxyribonucleotides
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NDPs-->dNDP
Enzyme is ribonucleotide reductase. Only happens at nucleoside diphosphate level. Source of reducing equivalents is NADPH. Inhibited by dNTPs and dNDPs. |
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Deficiencies in THF
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Vitamin B12 is needed to regenerate THF from C metabolite. With low levels of folate, lack of B12 is evident since you can't regenerate folate so you get anemia.
If you supplement with folic acid, don't notice when you're out of B12 until late onset effects quick in: neuronal damage. Already screwed. |
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Salvage Pathways
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Nucleic acids constantly being broken down, need a way to reuse nucleosides and nitrogenous bases.
For purines, one pathway to reuse nucleosides and nitrogeneous bases. Nucleoside kinases recycle nucleosides. Phosphoribosyl transferase recycle bases. EX: HGPRTase (hypoxanthine guanine phosphoribosyl transferase) or thymine kinase. |
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Role of Salvage Pathways
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1) Prevent waste/loss of nucleotide degradation products
2) More important source of nucleotides than biosynthetic in some tissues 3) Required to activate certain purine analog metabolites |
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Degradation of Purine Nucleotides
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1) - Degradation requires deaminases to remove the amino groups
EX: Guanine deaminase turns guanine into xanthine. 2) - A nucleotidase to remove the phosphates EX: dAMP to dA using nucleotidase. 3) - A phosphorylase to remove ribose EX: Adenosine to adenine and ribose 1 –Pi using a purine nucleoside phosphorylase (adenosine phosphorylase) 4) - An oxidase (xanthine oxidase) to dispose of the purine ring. End product of the reaction is uric acid (pretty insoluble). EX: Adenine Guanine Uric Acid (both steps catalyzed by xanthine oxidase, produces H2O2!) Deamination can occur at nucleotide or nucleoside level (adenylate deaminase or adenosine deaminase) |
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General Points about Purine Degradation
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1) 1) Breakdown of purines (and pyrimidines) nucleotides to nucleosides and free purine bases is quantitatively significant in most tissues
2) 2) Can salvage those nucleosides and free purine bases. Most of the time this happens, only a fraction goes all the way to uric acid. |
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Degradative Pathway Defects
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Adenylate Deaminase (muscle weakness, exercise intolerance)
Adenosine Deaminase (severe combined immunodeficiency) Purine nucleoside phosphorylase (Selective cellular immunodeficiency) |
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Salvage Pathway Defects
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Partial HGPRTase deficiency (high serum urate, gout)
Complete HGPRTase deficiency (high serum urate, severe retardation, self harm, known as Lesch Nyhan Syndrome) |
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Adenylate Deaminase Deficiency
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-Enzyme plays role in purine nucleotide cycle, in deaminating AAs
-Helps keep adenylate kinase in action. AMP inhibits, so adenylate deaminase turns it into IMP is converted to GTP, then GDP Evidence: -10x more conc. isoenzyme in muscle - Muscle contraction leads to NH3 buildup, but this disappears when you have adenylate deaminase deficiency - Lack of adenylate deaminase leads to muscle weakness |
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Adenosine Deaminase Deficiency
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Acts on adenosine and deoxyadenosine. Adenylate deaminase is selective for AMP. When you have deficiency, you no longer have a way of processing deoxyadenosine, which accumulates.
This aggregates even more in lymphocytes (high nucleotide kinase levels) dATP accumulation inhibits ribonucleotide reductase, inhibiting DNA synthesis in lymphocytes. Immunodeficiency!! |
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Antimetabolite
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Structural analog of metabolite, competes with using normal one.
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Antibiotic
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Substance produced by one microorganism that interferes with growth/metabolism of other microorganisms.
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Sulfonamides
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Sulfur drugs are first used antimetabolites. Resemble P-aminobenzoic acid (PABA). Bacteria use PABA to make folic acid. Sulfur analogs prevent bacteria from making folic acid, kills them. PABA has no role in humans, so drugs don’t do anything.
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Methotrexate
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Block one carbon metabolism. Block purine and dTMP.
Methotrexate (MTX) is an analog of folic acid. 1) Mechanism of action: like folic acid, so it is competitive inhibitor of dihydrofolate reductase This leads to lower levels of THF and all 1C derivatives of it (A, B, C) 2) Lack of these substrates leads to lack of dTMP synthesis (so no DNA synthesis) and lack of purine synthesis. 3) Antidote: folinic acid (leucovorin), derivative of THF, will protect against toxicity Folinic acid can completing the reactions inhibited by MTX. |
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6-Mercaptopurine
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Inhibitor of purine synthesis.
1) Action In body, activated to thioIMP (T-IMP) by HGPRTase, which is an IMP analog b) Blocks utilization of IMP as a substrate (competitive inhibitor) c) Mimics role of IMP as feedback inhibitor of purine synthesis, so blocks purine synthesis Mechanisms of Resistance: 1) Decreased activation (loss of HGPRTase in the tumor cells) 2) Increased degradation: seen occasionally because of increase in TPMT or xanthine oxidase (both remove 6MP from body) |
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5-Fluorouracil
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Inhibitor of DNA synthesis.
1) Action Requires lethal synthesis (i.e. activation to make effective) to a 5’fluoro analog of UMP, and eventually dUMP. b) Metabolized like uracil c) Competitive inhibitor of thymidylate synthase: binds tightly to active site, but not acted upon d) Decreased synthesis of dTMP leads to decrease in dTTP, so less synthesis Works especially well with leucovorin. Degraded by dihydropyrimidine dehydrogenase. Resistance: ) Increased specificity of thymidylate synthase to discriminate between dUMP and d5’FUMP b) Overproduction of thymidylate synthase in the cell c) Increased levels of degrading enzyme |
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Cytosine Arabinoside
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Inhibitor of DNA synthesis.
1) Action requires lethal synthesis (activation by deoxycytidine kinase) AraCDP interferes with deoxynucleotides. It is a competitive inhibitor of ribonucleotide reductase AraCTP is an analog of dCTP, so is competitive inhibitor of dCTP in DNA synthesis. Direct inhibition of DNA synthesis is the most important of its two effects. |
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Gemcitabine
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Related to cytosine arabinoside.
a) Activation similar to cytarabine b) dFCTP is weak inhibitor of DNA polymerase c) Inhibits ribonucleotide reductase d) Incorporated in DNA, acts as inhibitor of DNA chain elongation e) Inhibits DNA repair f) Its inhibition of DNA repair activity makes it effective in combination with DNA damaging chemotherapeutic |
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Herceptin
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Used in tumors overexpressing Her2/neu, a tyrosine kinase receptor.
A humanized monoclonal antibody, inhibits growth of Her2 overexpressing cells. It alone can cause regression of metastatic breast cancer. |
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Tamoxifen
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Effective against estrogen receptor positive breast cancers (overexpression of ER). Competitive inhibitor. No good after 5 years.
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Aromatase Inhibitors
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Aromatase essential for synthesis of estrogen in fatty tissues. Use after 5 years of tamoxifen. Slight advantage when combined.
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Two targets of drug design
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1) Inhibit active site, deep cleft, small molecule. Use screening
2) Protein surface, large protein or peptide are better suited. |
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Saquinivir
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HIV drug that target HIV RNA protease.
Asp 25 is cleaving AA. Saquinivir fits into cleft but can't be split. Resistance is big problem, since 80% of people have resistance to at least one antiretroviral. Because HIV reverse transcriptase has high error rate, keep on subtly changing HIV protease. Change in shape means drug doesn't bind well anymore. The closer the drug is to the substrate (rather than to the cleft), the more resistant to mutations. Balance between extra affinity and resistance. |
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HIV-1 fusion inhibitors
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Target is HIV surface, prevent interaction with cell surface.
Target is GP41, expressed on HIV. Binds CD4 on host cell. Conformational change brings parts closer together. Fuzeon derived from peptide sequence. Imitate fused structure so shape change doesn't have. But you need loads of it (as much as HIV molecules). Stabilize helix to make better competitive inhibitor. |
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Gleevec
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Small molecule for active site.
drug for chronic myelogeneous leukemia. Kinase inhibitors. Hard to compete with kinase active site. When you compete with ATP site, lose specificity. Gleevec targets ATP site in inactive state. Only binds a few kinases other than abl. |
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Tamiflu
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Inhibitor of flu protein neuraminidase. The protein removes sialic acid. This is key to letting new viruses out. Tamiflu binds neuraminidase tighter than sialic acid. Since we're adding bonds to enzyme, leads to resistance!
H1N1 patients resistant to tamiflu, but not relenza. |
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Cushing's Syndrome
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Overarching term for high cortisol.
Moon face, buffalo hump, high sugar, muscle wasting. Low serum potassium. |
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Autonomous Adrenal Tumor
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Adrenal cortex releases too much cortisol, ACTH is not signaling.
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Ectopic ACTH Tumor
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High levels of ACTH trigger cortisol release. Does not respond to dexamethasone.
High 17 KS. |
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Cushing's Disease
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High ACTH
Death to Mexicans heals it. Excess ACTH comes from pituitary. High 17 KS. |
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Purine Metabolism Disorder (leading to gout)
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Treat with sulfanpyrazone in short term, allopurinol in long term.
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