biochem_mod_6

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soren101
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biochem_mod_6
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2011-03-09 19:36:08
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biochem mod6 muscoloskeletal ms1
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biochem mod6 ms1
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  1. RECOGNIZE PLANDROMIC SEQUENCE
    • GGATCC
    • CCTAGG
  2. STEPS IN CONSTRUCTING RECOMB DNA MOL
    1) RESTRICTION ENDONUCLEASES -- CLEAVE 2X DNA TO CREATE STICKY/BLUNT ENDS

    2) VECTORS

    3) CONTRIBUTING DNA
  3. 3 CLASSES OF VECTORS
    1) PLASMID -- SMALL EXTRACHROM, CIRCULAR DNA MOL THAT REPLICATES INDEPENDENTLY. CONFERS Ab RESISTANCE

    2) PHAGES -- LINEAR DNA MOLS THAT USE BAC AS HOST

    3) VIRUSES -- USE MAMMALIAN CELLS AS HOST
  4. SHOTGUN GENOMIC vs cDNA CLONING
    • GENOMIC
    • CHROM DNA INCLUDING INTRONS --> RESTRICTION NUCLEASE DIGESTION CREATES DNA FRAGS --> CLONING --> STILL WITH INTRONS

    • cDNA
    • mRNA --> REVERSE TRANS AND DNA CLONING --> cDNA (NO INTRONS)
  5. PRINCIPALS OF MOLECULAR HYBRIBIZATION
    1) ANNEALING PROPERTIES OF 2 COMPLEMENTARY STRANDS. H-BONDS

    2) DOUBLE HELIX ONLY WHEN STRANDS PERFECT COMPLEMENT. IF NOT, THEN KINK WILL FORM
  6. SOUTHERN vs NORTHERN vs WESTERN BLOT
    • SOUTHERN
    • 1) DETERMINES IF GENE PRESENT IN TISSUE (DNA)

    2) DETERMINE COPY NUMBER OF GENE

    3) DETERMINE GROSS ALTERATIONS IN A GENE

    • NORTHERN BLOT
    • 1) DET ID GENE EXPRESSED AS mRNA

    2) DET STRUCTURAL ALTERATION IN mRNA MOL

    • WESTERN
    • USE Ab TO DETECT PROT OF INTEREST
  7. MICROARRAY ANALYSIS
    SIMULTANEOUS DETECTION OF EXPRESSION STATUS OF NUMEROUS GENES USING NUC ACID HYBRIDIZATION

    ex -- COMPARISON OF mRNA EXPRESSION OF NORMAL (GREEN) vs CANCEROUS (RED) CELLS AND UNDIFFERENTIATED vs DIFF CELLS

    • GREEN -- NORMAL MAKES MORE
    • RED -- CANCER MAKES MORE
    • DARK/BLACK -- NEITHER PRODUCES

  8. PRINCIPLES OF PCR
    REPEATED COPYING OF x2 DNA --> AMPLIFICATION

    1) SEPARATION USING HEAT

    2) HYBRIDIZATION OF 2 SPECIFIC PRIMERS MADE OF SHORT COMP STRANDS

    3) DNA SYNTH USING HEAT STABLE POL

    4) REPEAT 1-3
  9. DETECTION OF SICKLE CELL USING SOUTHERN BLOT
    A TO T TRANSVERSION IN b-GLOBIN GENE DESTROYS RECOG SITE OF RESTRICTION ENDO.

    SS HOMO HAS LARGER SINGLE DNA FRAG THAN NORM (2 FRAGS)
  10. DETECTION OF b-THALASEMIA USING SOUTHN BLOT
    DELETION OF b-GLOBIN CHAIN CAUSING SHORTER FRAG THAN NORM
  11. DETECTION OF CYSTIC FIBROSIS USING PCR (case)
  12. USE OF PCR TO DETECT INFECTIONS AGENTS
    H1N1 AND HIV INFECTION -- AMPLIFY VIRAL DNA

    INVASIVE CANDIDIASES
  13. REGULATION OF GENE EXPRESSION AND GENE THERAPY
    1) PROMOTER BLOCKING -- INTRODUCING FAKE PROMOTER WITH HIGH AFFINITY FOR TRANSCRIPTION FACTORS SO DIVERTING AWAY FROM REAL PROMOTERS

    2) ANTISENSE NUCLEIC ACID -- COMP OLIGONUCS TO KNOWN SEQUENCE OF mRNAs OF SELECTED GENES CAN BE USED TO INH TRANSLATION OF SPECIFIC mRNAs.

    • 3) GENE REPLACEMENT THERAPY:
    • --DNA INTROed INTO CELL BY INTENSE ELECT FIELD

    --NON-IMMUNOGENIC LIPID COMPLEXES THAT HELP DNA ENTER CELL

    --RECEPTOR MEDIATED ENDO BY COVALENT LINKAGE TO LIGAND

    --VIRAL VECTORS INCLUDE LTR, GAG, POL, ENV
  14. GENE THERAPY FOR SCID
    ABSENCE OF FUNC T, B, AND NK CELLS. DEFECT IN CYTOKINE RECEPTOR gc GENE

    RETROVIRAL VECTOR INSERTED INTO STEM CELLS in vitro THEN RE-INFUSED BACK INTO PATIENT

    RANDOM INSERTION OF VECTORS INTO CHROM LEAD TO DEATH
  15. GENE THERAPY FOR X-LINKED CGD
    RANDOM VECTOR INSERTION LEAD TO POSITIVE OUTCOME
  16. FUNCTION OF MICROTUBES IN MITOSIS, INTRACELLULAR TRANSPORT/SECRETION, CELLIA AND FLAGELLA, AND PSEUDOPODIAL MOVEMENT
    MITOTIC SPINDLE

    INTERPHASE MICROTUBULE NETWORK GUIDES THE MOVEMENT OF VESICLES AND ORGANELLES; INVOLVED IN INTRACELLULAR TRANSPORT/SECRETION

    FORM AXONEMES OF CILIA AND FLAGELLA
  17. DYNAMIC INSTABILITY OF MICROTUBES
    CONSTANTLY GROW AND SHRINK

    ONLY PLUS ENDS

    ALLOWS MICROTUBES TO EXPLORE ENV

    DYN BEHAVIOR STOPS WHEN BIND TO TARGET STRUCTURES

    SIGNAL GIVEN THAT ALLOWS CHROM TO SEPATATE AND ANAPHASE BEHINS

    WITHOUT DYN, THOUSANDS OF MICROTUBES WOULD HAVE TO FORM TO MAKE CERTAIN EACH CHROM IS CONNECTED
  18. TUBULIN
    DIMER OF POLYPEPTIDES CALLED a AND b

    ARRANGED END TO END

    3rd FORM CALLED g-TUBULIN FOUND IN CENTROSOMES AND ACTS AS MICROTUBULE "ROOT" & NUCLEATES MICROTUBES
  19. 3 UNUSUAL ASPECTS OF TUBULIN
    1) BIND SITE FOR LARGE VARIETY OF LIGANDS

    -a & b BIND GTP FOR MICROTUBE ASSEMBLY. ONCE ADDED, GTP HYDROLYSED TO GDP, THEN REPEAT

    -OTHER BINDINGS SITES FOR COLCHICINE, VINCA, AND TAXANE

    2) C-TERM REGIONS OF a AND b HIGHLY NEGATIVELY CHARGED

    -CONSIST LARGELY OF GLUT AND ASP RESIDUES

    -STICK STRAIGHT OUT; MAY PLAY ROLE IN SIGNALING

    3) NUMBER AND NATURE OF POST-TRANSLATIONAL MODS

    -LYS40 OF a-TUBE ACETYLATED FOR STABILITY (AXON)

    -a-TUBE SYNTHED WITH C-TERM TYROSINE RES (REMOVED BY TUB CARB-PEP AND REPLACED BY TUB TYR LIGASE) FORM PEPTIDE BOND NON-RIBOSOMALLY. TYR SIGNAL TO REG STABILITY (NO TYR = MORE STABLE)

    - BOTH a & b POLYGLYCYLATED. MAY RESULT IN UNUSUAL DOUBLET MICROTUBES
  20. TAXANES AND VINCA ALKALOIDS
    BLOCK DYNAMIC INSTABILITY

    MOST SUCCESSFUL CANCER THERAPY AVAILABLE

    TAXANES USEFUL IN BREAST, OVARIAN, AND LUNG CANCER

    VINCA USEFUL IN HODGKIN AND ACUTE LYMPHOCYTIC LEUKEMIA
  21. ROLE OF COLCHICINE IN GOUT
    EXCESS URIC ACID PRODUCTION AND DEPOSITION AS CRYSTALS IN JOINTS

    WHITE BLOOD CELLS RELEASE INF FACTORS

    COLCHICINE FOR ACUTE GOUT BINDS TO TUBULIN MOLS AT PLUS ENDS AND FREEZES DYNAMICS

    TARGETS WBCs TO LOSE PSEUDOPODIAL MOTILITY SO CANNOT MIGRATE TO JOINTS

    IF IN JOINTS, PREVENTS SECRETION OF ORGANELLES CONTAINING INF FACTORS
  22. FUNCTIONS OF MAPS
    LONG FILAMENTOUS PROTS LACKING ENZ ACT THAT BIND TO C-TERM REGIONS OF MICROTUBES

    PROMOTER DOMAIN THAT BINDS TO MICROTUBE AND PROJECTION DOMAIN THAT STICKS OUT

    • PROMOTERS INDUCE GROWTH, INH DYN
    • INSTABILLITY

    PROJ INDUCE SPACING AND REG VELOCITY OF MOTOR PROTS THAT TRAVEL ON MICROTUBULES

    PHOS OF MAPS MAKES THEM MORE NEG --> MICROTUBES ALSO NEG, SO DIMINISHES INTERACTION
  23. ROLE OF TAU IN ALZ
    SENILE PLAQUES MADE OF AMYLOID PROT; PAIRED HELICAL FILAMENTS MADE OF TAU WHICH IS HYPERPHOSED

    TAU TOO NEG TO BIND AND STABILIZE NEURONAL MICROTUBES

    INSTEAD SELF-ASSEMBLES TO FORM PAIRED HELICAL FILS

    NEURONAL TUBES BEGIN TO SHRINK AND ARE UNABLE TO TRANSPORT SYN VESICLES --> DEMENTIA
  24. MOTOR PROTS POWERED BY ATP HYDROLYSIS
    KINESIN, CYTOPLASMIC DYNEIN, AND AXONEMAL DYNEIN

    KINESIN CARRIES CARGO IN ANTEROGRADE DIRECTION

    DYNEIN - RETROGRADE

    AXONEMAL DYNEIN POWERS CILIARY AND FLAGELLAR MOTILITY
  25. KARTAGENER'S SYND
    GENETIC

    LESIONS IN AXONEMAL DYNEIN

    CILIA AND FLAG CANNOT MOVE. SPERM AND MUCUS ELEVATOR IMMOBILE

    MALE INFERT, FREQ BRONCH INF, IN 50% SITUS INVERSUS TOTALIS
  26. HEREDITARY SPASTIC PARAPLEGIA
    INC SPASTICITY AND NEUROMUSCULAR WEAKNESS, ESP IN LOWER EXT

    MUTATED KINESINS

    ONE TYPE ATPase ACTIVITY INH SO KINESIN CANNOT WALK ON THE MICROTUBE

    MOSTLY IN NEURONS --> INH ANTEROGRADE TRANS
  27. BARDET-BIEDL SYND
    MUTATION IN INTRAFLAGELLAR RAFT

    G-PROT REC DO NOT GET INTO THE PRIMARY CILIA AND SIGNALING COMPROMISED --> DEV PROBS

    RETINOPATHY, CARDIOMYOPATHY, POLYDACTYLY, HYPOGONADISM, M&PR, AND OBESITY
  28. HYDROCEPHALUS
    1 IN 500 LIVE BIRTHS

    ACCUMULATION OF CSF

    ONE FACTOR IS LACK OF HYDIN PROT --> PART OF CILIARY AXONEMES --> AXON MOTILITY

    BEATING OF CILIA IRREGULAR AND UNABLE TO PUMP CSF OUT OF VENTRICLES
  29. ADVANTAGES OF ADENOVIRUS VECTOR
    INFECT WIDE RANGE OF CELL TYPES

    UNLIKE RETRO, CAN TRANSFER INTO NON-DIVIDING CELLS

    GENERALLY NON-INTEGRATING (EPISOMAL)

    DISADVANTAGES

    EPISOMAL VECTORS OFTEN LOST AFTER CELL DIVISION

    IMMUNOGENIC

    INSERT INTO WIDE RANGE, THUS HARD TO TARGET SPECIFIC CELL TYPES
  30. BASIC FEATURES OF COLLAGEN STRUCTURE
    MOST ABUNDANT PROT; HIGH TENSILE STRENGTH

    SUBUNITS CALLED TROPOCOLLAGEN. FORM POLYMERS --> FIBERS OR NETWORKS. FIBERS ARE 3 POLYPEP CHAINS FORMING TRIPLE HELIX

    FIBERS COVALENTLY CROSS-LINKED TO EACH OTHER AND WITHIN x3 HELIX

    INDIVIDUAL T. COLL IN x3 HELIX HAS HELICAL SHAPE CALLED TYPE II TRANS HELIX. STABILIZED BY STERIC REPULSION USING PROLINE, MANY OF WHICH ARE HYDROXYLATED FORMING 4-HYD.PROLINE THAT H-BOND

    LYSINE IN COLLAGEN HYDROXYLATED TO MAKE HYD.LYSINE --> ATTACHMENT POINT FOR GALACTOSE AND GLUCOSE --> H-BOND AND CROSS-LINK FOR STABILIZATION

    GLYCINE = 1/3 OF COLLAGEN; EVERY 3rd POSITION. POINT TOWARD CENTER OF HELIX. IF OTHER AA, SIDE CHAIN WOULD CREATE BULGE AND DESTABILIZE
  31. BIOSYNTH OF COLLAGEN
    MANY POST TRANSLATIONAL MODS

    1) PREPROCOLLAGEN SYNTHED ON RIBOS OF RER. NEEDS O2 AND ASCORBIC ACID (VIT C) AS CO-FACTOR FOR SERIES OF HYDROXYLATIONS

    2) PREPROCOLLAGEN ENTERS LUMEN OF ER. SUGARS ARE ADDED (GLUC & GAL) --> OLIGOSACC ADDED AND RELEASED INTO LUMEN OF ER --> 3 GLUC REMOVED AND DISULFIDE BRIDGES FORM AND x3 HELIX MADE SPONT. --> NOW PROCOLLAGEN

    3) SECRETION OF PROCOLLAGEN FROM CELL --> ENTERS GOLGI WHERE SUGARS ADDED/REMOVED

    4) PROCESSED IN EXTRACELLULAR MATRIX --> CLEAVAGE OF N & C-TERM REGIONS AND WHAT REMAINS IS TROPOCOLLAGEN --> IF DENATURED, x3 HELIC WILL NOT REFORM (JOB OF C-TERM)

    5) FORMATION OF COLLAGEN FIBER BY SPONT. POLYMERIZATION, N & C-TERM HELPED PREVENT THIS

    6) CROSS-LINKING OF FIBERS. LYSYL OXIDASE REQUIRES COPPER AND DOES NOT DIRECTLY MAKE CROSS-LINKS --> CLEAVES a-NH2 GROUP MAKING ALDEHYDE DERIVATIVE OF LYSINE OR HYDROXYLYSINE (VERY REACTIVE (O2))
  32. OSTEOGENESIS IMPERFECTA
    VARIOUS FORMS OF COLLAGEN MUTATION (a1(I) OR a2(I) COLLAGENS)

    ONE LETHAL FORM, MUTATION REPLACES GLYCINE WITH ALANINE --> SMALL CHARGE DISRUPTS x3 HELIX --> PROTEOLYTIC DIGESTION --> INFANTS MINIMAL BONE MINERALIZATION AND DIE SOON AFTER BIRTH
  33. EHLERS-DANLOS SYNDROME
    MUTATION IN COLLAGEN SYNTH PATHWAY

    HYPER-EXTENSIBILITY

    TYPE IV: DEFECT IN a1(III) COLLAGEN

    TYPE VI: DEFECT IN LYSYL HYDROXYLASE
  34. SCURVY
    NUTRITIONAL DISORDER CAUSED BY LACK OF ASCORBIC ACID (VIT C)

    LOSS OF TEETH, BLEEDING, FATALITY

    • NEEDED FOR:
    • 4-PROLYL HYDROXYLASE
    • 3-PROLYL HYDROXYLASE
    • LYSYL HYDROXYLASE
  35. OILED COIL MODEL OF ELASTIN
    SHORT REPEATING SEGS OF SMALL HYDROPHOBIC AAs

    HIGHLY CROSS-LINKED USING LYSYL OXIDASE

    OILED COIL: UPON STRETCHING, SIDE CHAINS EXPOSED TO AQUEOUS ENV AND DESTABILIZED. WHEN PRESSURE RELEASED, RETURN TO ORIGINAL SHAPE
  36. COPPER IN SYNTH OF COLLAGEN AND ELASTIN
    COLLAGEN STEP 6) LYSYL OXIDASE NEEDS Cu TO REMOVE a-NH2 GROUP AND INDUCE REACTIVITY OF LYSINE/HYDROXYLYSINE

    LYSYL OXIDASE USED SIMILARLY IN ELASTIN
  37. ROLE OF FIBRILLAN IN MARFAN SYNDROME
    ELASTIN MONOMERS POLYMERIZE TO FIBERS MADE OF PROT CALLED FIBRILLIN

    MUTATIONS IN FIBRILLIN CAUSE MARFAN

    CONNECTING ELASTIN MONOMERS???
  38. WHAT IS GLYCOPROTEIN
    PROT THAT HAS CARBS COVALENTLY ATTACHED

    CAN BE SINGLE SUGAR OR OLIGOs
  39. WHAT ARE OLIGOSACCHARIDES
    SMALL GENERALLY WELL-DEFINED POLYMER OF DIFF SUGARS

    ARRANGEMENT USUALLY NON-RANDOM
  40. WHAT ARE GLYCOS-AMINO-GLYCANS
    LINEAR POLYMER OF REPEATING DISACCHARIDE UNITS OFTEN BEGINNING WITH CORE NON-REPEATING STRUCTURE

    DIFFERENCE BETWEEN GLYCOSAMINOGLYCANS AND OLIGOs IS THAT GAGs HAVE UNDEFINED AND RELATIVELY LARGE NUMBER OF SUGARS
  41. WHAT ARE PROTEOGLYCANS
    PROTS WHICH A GAG IS COVALENTLY ATTACHED
  42. TO WHICH PROT RESIDUES DO N AND O-LINKED OLIGOs ATTACH?
    N-LINKED: OLIGOs ATTACH TO AMIDE NITROGEN OF ASPARAGINES

    O-LINKED: OLIGOs ATTACH TO HYDROXYL OXYGEN OF SERINE, THREONINE, OR HYDROXYLYSINE
  43. SUGARS INVOLVED IN SYNTH OF OLIGOs AND GAGs ARE CARRIED ON WHAT?
    NUCLEOTIDES
  44. WHAT IS DOLICHOL AND WHAT IS ROLE IN OLIGO SYNTH
    EXTREMELY HYDROPHOBIC ISOPRENOID

    MADE AS A DETOUR FROM THE CHOL SYTH PATHWAY

    ANCHORED IN MEM OF ER

    SUGARS ATTACHED TO LIPID (DOLICHOL) NOT PROTEIN! ON CYTO SIDE OF ER --> FLIPS TO ER SIDE AND OLIGOs TRANSFERED FROM DOLICHOL TO ASPARAGINE RESIDUE ON PROT

    DOLICHOL THEN DE-PHOSED AND FLIPS BACK TO CYTO SIDE FOR ANOTHER ROUND
  45. GENERAL OUTLINE OF N-LINKED OLIGO SYNTH (4 STAGES)
    1) BIOSYNTH OF SUGER COMPONENTS: SUGARS SYNTHED AND ATTACHED TO NUCLEOTIDE.

    • UDP - GLU, FAL, GlcNAc, GalNAc
    • GDP - Man, Fuc
    • CMP - SA

    2) SYNTH OF LIPID-LINKED OLIGOs: SUGARS ATTACHED ONE-BY-ONE TO DOLICHOL CORE ON CYTO SIDE OF ER MEM --> FLIPS TO LUMEN-SIDE OF ER

    3) TRANSFER OF OLIGOs TO PROT: FROM DOLICHOL TO ASPARAGINE RESIDUE ON PROT

    4) PROCESSING OF PROT-BOUND OLIGOs IN GOLGI: MANY SUGARS REMOVED LEAVING OLIGO CORE --> SUGARS ADDED BACK TO FORM EITHER THE COMPLEX OR THE HIGH MANNOSE STRUCTs OR SOME HYBRID OF THEM

    IF GOING TO LYSOSOME, 2 MANNOSE-6-PHOSs ADDED WHICH ARE RECOGNIZED BY M-6-P RECEPTOR
  46. O-LINKED OLIGO STRUCTURAL DIFFs IN TYPE O, A, AND B BLOOD
    GLYCOPROTEINS

    SUGARS ADDED TO OLIGO CALLED H ANTIGEN

    DOES NOT INVOLVE DOLICHOL

    • O: BARE
    • A: GalNAc
    • B: Gal
  47. FUNCTIONS OF PROT-BOUND OLIGOs (4)
    1) PROTECT PROTS FROM DEGRADATION

    2) HELP TARGET PROTEINS

    3) CELL-CELL RECOGNITION

    4) MAY HELP DETERMINE CONFORMATION OF PROT
  48. ROLE OF HEMAGGLUTININ, NEURAMINIDASE, AND SIALIC ACID RESIDUES IN INFLUENZA
    HEMA: BINDS TO SIALIC ACID CAUSING RECEPTOR MEDIATED ENDOCYTOSIS

    NEURA: CLEAVES SIALIC ACID TO FREE NEW VIRUSES FROM CELL
  49. I-CELL DISEASE AND ROLE OF MANNOSE 6 PHOS
    DEFICIENCY OF N-ACETYLGLUCOSAMINE-1-PHOSPHOTRANSFERASE WHICH CREATES M6P

    LYSOSOME UNABLE TO DEGRADE GAGs WHICH ACCUMULATE IN CELLS AS INCLUSION BODIES
  50. a&b-MANNOSIDOSIS, FUCOSIDOSIS, SIALIDOSIS, AND ASPARTYL-GLUCOSAMINURIA
    DEFECTS IN DEGRADATION OLIGOs IN LYSOSOME

    MENTAL RETARDATION CAUSED BY ACCUMULATION AND EXCRETION OF INCOMPLETELY DIGESTED OLIGOs
  51. TYPES OF GAGs AND LIKELY ROLES
    HYALURONIC ACID: NOT ATTACHED TO PROTS AND CONSISTS OF REPEATING DISACC MANDE OF GlcNAc AND GLUCURONIC ACID. HUGE MOLECULE FUNCTIONS AS LUBEF AND SHOCK ABSORBER IN JOINTS AN MAJOR PART OF VITREOUS HUMOR OF EYE

    CHONDROITIN SULFATE: TENSILE STRENGTH OF CARTILAGE, TENDONS, LIGS, AND WALL OF AORTA

    HEPARIN SULFATE: SPONGY QUALITY TO BASEMENT MEMBRANE
  52. GAGs ARE HIGHLY NEGATIVE AND ABSORB WATER READILY & FORM GELS
    KNOW THIS
  53. SYNTHESIS OF GAGs AND HOW DIFF FROM SYNTH OF OLIGOs
    SUGARS ATTACHED SEQUENTIALLY TO SERINE AND ASP OF PROT CORE

    SUGARS ALWAYS BOUND TO UDP PRIOR TO ATTACHMENT

    SULFATES ADDED

    BOTH GAGs AND OLIGOs METABOLIZED IN LYSOSOMES
  54. SYNDROMES THAT INVOLVE DEFECTIVE DEGRADATION OF GAGs IN LYSOSOMES
    HURLER

    HUNTER

    SANFILIPPO

    MORQUIO

    MAROTEAUX-LAMY

    SLY
  55. ETIOLOGY OF CONGENITAL MUSCULAR DYSTROPHY AND FUNCTION OF DYSTROGLYCAN
    DEFECTIVE GLYCOSYLATION OF DYSTROGLYCAN

    DG IS A PROT THAT BRIGDES CELL MEM. EXTERNALLY, DG BINDS TO COMPS OF EXTRACELLULAR MATRIX -- INTERNALLY BINDS TO DYSTROPHIN WHICH BINDS TO ACTIN

    MUSCLE WEAKNESS AND SEVERE NEUROPATHY
  56. FIBRONECTIN
    ADHESIVE PROT

    DIMER OF 2 CHAINS CONNECTED BY DISULFIDE BRIDGES

    BINDING SITES FOR HEPARIN, GANGLIOSIDES, FIBRIN, COLLAGEN AND INTEGRINS.

    INTEGRINS IMPLANTED IN CELL MEMs, FIBRONECTIN AND LINK THEM W/ COLLAGEN AND HELP SHAPE CELLS OR GROW IN CERTAIN DIRECTIONS

    IMPORTANT IN BLOOD COAGULATION. LACK CAN LEAD TO HEMOPHILIA

    TUMOR CELLS PRODUCE LESS FIBRIN --> BREAK FREE (METASTASIZE)

    STAPH AND STREP CONTAIN FIBRONECTIN RECEPTORS --> INC INFECTIVITY AND PENETRATE EXT MATRIX
  57. LAMININ & ENACTIN
    ADHESIVE PROT FOUND IN BASAL LAMINA

    FLEXIBLE THIN MATS THAT SURROUND EPI SHEETS & TUBES, MUSCLE FAT & SCHWANN CELLS.

    3 CHAINS (a, b, g) ARRANGED TO FORM A CROSS

    BIND TO TYPE IV COLLAGEN, ENTACIN, HEPARIN, HEPARAN SULFATE, AND INTEGRINS

    STIMS NERVE AXON GROWTH IN EMBRYOS

    ENACTIN WITH LAMININ, T-IV-C AND OTHER PROTEOGLYCs FORM BL
  58. VITRONECTIN
    ADHESIVE PROT

    BLOOD BONE OTHER TISSUES

    LIKE FIBRONECTIN TO MEDIATE CELL ADHESION TO EXTRACELLULAR MATRIX AND PROMOTE BLOOD COAG
  59. THROMBOSPONDIN
    ADHESION PROT

    ENCODED BY 3 DIFF GENES AND SUBJECT TO ALT mRNA SPLICING

    PRODUCED BY PLATELETS AND OTHER CELLS

    STIM CELL PROLIFERATION IMPORT PART OF WOUND HEALING AND NERVE GROWTH

    INHIBIT DEV OF NEW CAPILARIES

    PROD BY MACROPHAGES THAT ARE DESTROYING LEUKOCYTES THAT DIED BY APOP -- BIND THE DYING CELL TO MACROs
  60. CHONDRONECTIN
    ADHESION PROT

    BINDS CHONDROCYTES TO T-II-C TO PROTEOGLYCs OF CARTILAGE
  61. TENASCIN
    ADHESION PROT

    PROD LARGELY IN EMBRYO TISSUE

    BIND TO FIBRONECTIN AND SYNDECAN, A PROTEOGLYC BOUND TO CELL MEM

    PROMOTE OR INH CELL ADH

    REPELS GROWING NEURONS AND PLAYS ROLE IN REG OF CELL MIGRATION THAT IS IMP IN EMBRYO DEV
  62. DESCRIPTION OF INTEGRINS
    MEM PROTS THAT ACT AS RECEPTORS FOR EXTRACELL MATRIX PROTS.

    BIND TO ARG-GLY-ASP SEQUENCE IN ADHESIVE PROTS

    CONSIST OF 2 POLYPEP CHAINS (a, b) BOTH OF WHICH TRANSVERSE THE CELL MEM

    LINK EXTRACELLULAR MATRIX TO CYTOSKEL (LIKE A BRIDGE THROUGH CELL MEM, WITH OUTER PART BINDING TO ADHESIVE PROTS OF EXTRACELL MAT AND INNER PART TO CYTOSKEL PROT TALIN, VINCULIN OR a-ACTININ, WHICH BINDS TO ACTIN

    HIGHLY REGULATED -- EXTRACELL MAT SIGNALS CYTOSKEL & VICE VERSA
  63. FUNCTIONS OF INTEGRINS (6)
    1) PROMOTE BINDING OF CELL TO EXT MATRIX

    2) PLATELETS -- HELP THEM BIND TO FIBRONECTIN --> COAG

    3) MITOSIS -- IN CYTO DOMAIN OF FIBRONECT BINDING INTEGRINS IS PHOSED --> LOSE ABILITY TO BIND FIBRONECT. ALLOWS CELL TO TAKE SPHERICAL SHAPE REQUIRED FOR MITOSIS. "SIGNAL" TO OUTSIDE

    4) ON LEUKOCYTES -- DONT BIND EXT MATRIX. BIND ENDO CELL RECEPTORS AND ALLOWS LEUKOs TO CROSS THE ENDO LINING OF CAPILLARIES

    5) MECHANOCHEMICAL TRANSDUCERS -- ALLOW CHANGES IN EXT MAT STRUCT TO ALTER SHAPE OF CELL. "SIGNAL" FROM OUTSIDE

    6) BIND TO LAMININ -- ESP a6b4, STABILIZE SCHWANN CELLS SO THEY GEN MYELIN
  64. LEUKOCYTE ADHESION DEFICIENCY
    RARE MUTATION IN b2-INTEGRIN (CD18) EXPRESSED IN LEUKOCYTES.

    TROUBLE EXITING CAPILLARIES AND BINDING BACTERIA

    WOUND HEALING

    FAILURE TO PRODUCE PUS
  65. LEPROSY
    MYCOBACTERIUM LEPRAE

    BINDS TO LAMININ-2 (a2b1y1) IN NERVOUS SYSTEM, ALLOWING ACCESS

    ALSO BINDS INTEGRIN a6b4 ON SCHWANN CELLS --> ENTERS CELL WHICH LOSES MYELIN --> PERIPHERAL NERVES DIE
  66. KNOW THE REACTIVE OXYGEN SPECIES AND THE SOURCES OF THEIR PRODUCTION
    SUPEROXIDE ANION

    HYDROXYL RADICAL

    HYDROGEN PEROXIDE

    WHEN O2 REDUCED, TOXIC INTERMEDIATES PRODUCED AND REACT/DAMAGE

    REACTIONS WITH CARBS LEAST SERIOUS EXCEPT IN UNTREATED DIABETES SINCE THESE HAVE INC GLUC LEVELS --> CATARACTS

    MORE SERIOUS ARE LIPIDS, NUC ACIDS, PROTS
  67. STRUCTURE AND FUNCTION OF SUPEROXIDE DISMUTASE AND CATALASE
    • SOD CONVERTS SUPEROXIDE ANION INTO HYDROGEN PEROXIDE:
    • O2- + O2- + 2H+ --> H2O2 + O2

    3 FORMS: EXTRACELLULAR, CYTOSOLIC Cu-Zn, MITOCHONDRIAL MANGANESE (ONLY PROT KNOWN TO HAVE MANG, PROTECTS MITO)

    • CAT IS A HEME-CONTAINING ENZ THAT DESTROYS HYDROGEN PEROXIDE:
    • H2O2 + H2O2 --> 2 H2O + O2
  68. GLUTATHIONE PEROXIDASE
    ONE OF MOST UNUSUAL ENZ IN BODY, ACTIVE SITE CONTAINS AN ATOM OF SELENIUM IN THE FORM OF THE AA SELENOCYSTEINE

    BREAKS DOWN H2O2

    ONE ISOFORM PHGPX

    CAN ALSO REACT WITH PEROXIDES OF LIPIDS AND OTHER ORGANIC COMPOUNDS
  69. ROLE OF SELENIUM DEFICIENCY IN MALE INFERTILITY AND KESHAN DISEASE
    MALE INFERTILITY: GLUTATHIONE PEROXIDASE ISOFORM PHGPX ACTS TOGETHER WITH VIT E TO REVERSE PEROXIDE INDUCED DAMAGE TO MEMBRANES. CONCENTRATED IN TESTES AND SPERM CELLS. PHGPX LOSES ACTIVITY AND POLYMERIZES INTO CAPSULE TO PROTECT MITO (STRUCT INTEGRITY). WITHOUT, SPERM HEAD & TAIL FALL APART.

    KESHAN: RURAL CHINA WHERE SOIL IS POOR IN SELENIUM. CARDIAC FAILURE AT EARLY AGE DUE TO H2O2 DAMAGE. ALSO MUST HAVE DIETARY VIT C, E, AND Cu (OR INFECTION) FOR DISEASE. MACROs PRODUCE THESE INTERMEDIATES TO KILL BAC, SO INFECTION WILL EXACERBATE OXIDATIVE STRESS.
  70. STRUCTURE OF SELENOCYSTEINE AND HOW INSERTED INTO GLUTATHIONE PEROXIDASE
    IDENTICAL TO SERINE AND CYSTEINE AA EXCEPT WITH SELENIUM ATOM

    COTRANSLATIONAL MOD USING SPECIAL tRNA: AA-tRNA SYNTH --> SER-tRNA

    SERINE + tRNAsec + ATP --> SER-tRNAsec

    THEN SELENOCYSEINE (SEC) SYNTH REPLACES OH IN SER WITH SELENIUM --> SEC-tRNAsec

    mRNA FOR SEC HAS SPECIAL INSERTION SEQUENCE WHICH BINDS TO ITS PROTEIN AND CONVERTS UGA STOP CODON TO SEC CODON
  71. AAs IN GLUTATHIONE AND HOW CONNECTED
    TRIPEPTIDE (g-GLU-CYS-GLY)

    • DOES NOT USE RIBOSOMES.
    • GLUT + CYS + ATP --> g-GLU-CYS

    g-GLU-CYS + GLY +ATP --> GLUTATHIONE

    ASIDE FROM GLUTATHIONE PEROXIDASE, GLUTA FIXES DAMAGED HEMOGLOBIN BY REDUCTION AND REDUCES DISULFIDE BRIDGES
  72. ROLE OF OXYGEN TOXICITY IN CANCER, RETROLENTAL FIBROPLASIA, ISCHEMIA-INDUCED FREE RADICAL DAMAGE.
    EACH CELL DAMAGED 10,000 TIMES EVERY DAY BY OX TOX. DAMAGE --> MUTATION --> TUMOR. ALSO, INC H2O2 INCs TRANSCRIPTION OF MATRIX METALLOPROTEINASES WHICH DEGRADE COLLAGEN --> METASTASIS.

    • RETROLENTAL FIBROPLASIA:
    • PREMATURE INFANTS IN HYPERBARIC OXYGENINC O2 --> RETINAL DAMAGE & BLINDNESS

    IIFRD: DEC O2 --> INC XANTHINE OXIDASE --> THEN O2 RESTORED AND SUPEROXIDE ANIONS PRODUCED AND CAUSE DAMAGE. MAY DAMAGE PROTEOSOME WHICH CAUSES INC IN DAMAGED PROTS

    PHOTOAGING: UV LIGHT INC FREE RADICALS eg SUPEROXIDES IN SKIN --> SUPER OX DISMUTASE CONVERTS TO H2O2 --> INC MATRIX METALLOPROTINASES DEGRADE COLLAGEN --> WRINKLES

    AGE SPOTS: ACCUM OF PRODUCTS OF LIPID PEROXIDATION BY TOX OX
  73. HOW OX TOX USED FOR GOOD
    LEUKOs USE TO TARGET PATHOGENIC ORGANISMS

    APOPTOSIS USING CYTOCHROME C FROM MITO
  74. ROLES OF THIOREDOXIN AND GLUTATHIONE IN REDUCING DISULFIDE BONDS
    THIOREDOXIN USES SELENOCYSTEINE RESIDUE TO ACT AS A SENSOR TO DETECT REACTIVE OX SPECIES AND THEY INC ITS ACTIVITY (REDUCING aka BREAKING DISULFIDE BRIDGES)
  75. HOW DO SELENIUM DEFICIENCIES LEAD TO THYROID PROBS
  76. MECH OF ACTION OF CYTOCHROME P450 AND TYPES OF REACTIONS
    HYDROXYLATION OF MANY SUBSTRATES BY REACTIONS CALLED MONOOXYGENATIONS (PUTS 1 ATOM OF O2 INTO SUBSTRATE AND MAKES H2O WITH OTHER)

    2e- REQUIRED FOR EACH REATION, ACCEPTED FROM NADH OR NADPH

    TYPE OF REACTION DEPENDS ON WHERE e- INSERTED INTO ELEC TRANSPORT CHAIN
  77. COMPONENTS OF MICROSOMAL AND MITOCHONDRIAL P450 SYSTEM
    MICROSOMAL: IN SMOOTH ER, USES SINGLE NADPH-SPECIFIC P450 REDUCTASE ON MEM CONTAINING FAD AND FMN AS COFACTORS. MAKE COMPONENTS MORE HYDROPHILIC. USED IN DRUG AND XENOBIOTIC, STERIOD, FA, AND EICOSANOID METABOLISM

    NADPH --> FAD --> FMN --> P450

    MITOCHONDRIAL: INNER MEM OF MITO AND USED FOR STEROID METABOLISM. USES ADRENODOXIN REDUCTASE AND ADRENODOXIN CONTAINING FAD AND IRON-SULFATE PROT RESPECTIVELY TO HAND e- TO P450. MANY ISOFORMS (CYPs)
  78. ROLE OF CYTOCHROME P450 IN STEROID HORMONE SYNTH
    CYP11A1 CONVERTS CHOL TO PREGNONALONE

    SUBSEQUENT REACTIONS MAKE TESTOSTERONE, ALDOSTERONE, ESTRADIOL etc
  79. ROLE OF CYTOCHROME P450 IN DRUG AND XENOBIOTIC METABOLISM AS BOTH ACTIVATORS AND INACTIVATORS
    • TWO PHASES:
    • I -- FUNCTIONAL GROUP eg OH ADDED TO DRUG BY CYP450

    II -- CONNECT BY FUNC GROUP TO ENDOGENOUS SUBSTRATE eg GLUCURONIC ACID. MAKES DRUG MORE WATER SOLUBLE AND EASIER TO EXCRETE

    INACTIVATION: DRUG CONVERTED TO INACTIVE FORM eg VALIUM. CYP3A4 MAJOR PLAYER, LOC IN GI AND LIVER AND IS WHY ORAL DRUGS BROKEN DOWN SO FAST.

    ACTIVATION: eg TERFENADINE (SELDANE) ACTIVATED TO FEXOFENADINE (ALLEGRA) BY CYP3A4. TERFEN HAS SEVERE CARDIAC SIDE EFFECTS. GRAPEFRUIT JUICE INHIBITS CYP3A4 AND INC TERF []
  80. ROLE OF P450 POLYMORPHISMS IN DRUG METABOLISM
    LEVELS AND ACTIVITY OF P450 VARY IN PEOPLE AND GREATLY INFLUENCE EFFECT OF DRUGS.

    POLY = DIFF IN DNA SEQUENCE IN 1% OR MORE OF POPULATION. ex CYP2D6 DIVIDED AMONG POP INTO EXTENSIVE AND POOR METABOLIZERS. POOR AT RISK FOR ADVERSE DRUG REACTIONS WHILE EXTENSIVE MAY FIND DRUGS INEFFECTIVE.

    ex ANTIARRHYTHMICS, ANTIDEPRESSANTS, ANTIPSYCHOTICS, BETA-BLOCKERS, ANALGESICS
  81. BASIC CYP450 DRUG-DRUG INTERACTIONS
    UNINTENDED EFFECTS OCCUR WHEN LEVELS OF CYP450 ARE INC/INH BY OTHER DRUGS

    ex CYP2E1 IS INDUCED BY ALCOHOL OR ISONIAZID --> METABOLIZE SOME DRUGS INTO PROTS HARMFUL TO LIVER --> IMMUNE SYSTEM ATTACKS CAUSING FORM OF HEP. PEEPS WITH INC CYP231 AT HIGHER RISK.
  82. BASIC NO INVOLVEMENTS
    NO IS HIGHLY REACTIVE FREE RADICAL AND INVOLVED IN NEUROTRANSMISSION, VASODILATION, IMMUNE RESPONSE, PLATELET AGG, ERECTION, SEPTIC SHOCK, HYPOTENSION, VASC LEAK, AUTO IMMUNE -- RA ULCERATIVE COLLITIS DIABETES MS ASTHMA, GvsH DISEASE, LIVER CIRRHOSIS

    PRODUCED BY NO SYNTHASES
  83. BASIC NO INTERACTIONS
    ACTIVATES: SOLUBLE GUANYLYL CYCLASE

    INHIBITS: CYP450 HEMOGLOBIN, ACONITASE, MITO COMPLEXES I,II

    S-NITROSATION, OXIDATION

    NOx FORMATION

    SUPER OXIDE ANION PEROXYNITRITE FORMATION

    DNA STRAND CLEAVAGE, DEAMINATION
  84. HOW IS NO PRODUCED BY NOSs
    L-ARG + 2 MONOOXYGENATIONS SIMILAR TO CYTP450 OXIDOREDUCTASE SYSTEM
  85. ROLE OF CALMODULIN IN ACTIVATIONS OF NOSs
    e- PASSED FROM NADPH TO FAD TO FMN THEN TO HEME WHERE THEY ACTIVATE O2 FOR MONOOXYGENASE REACTION. BETWEEN FMN AND HEME IS CALMODULIN (CaM) BINDING SITE, WHICH MUST BE BOUND WITH CaM FOR e- TRANSFER.

    CaM BINDS WHEN INTRACELLULAR Ca INCed ABOVE BASAL.
  86. NOS ISOFORMS
    • ENDOTHELIAL NOS:
    • VASCULAR ENDO CELLS --> VASODILATION INH OF VASOCONSTRICTORS, INH OF PLATELET ADHESION AND AGG. INC Ca --> CaM BINDING --> MUSCLE LIGHT CHAIN KINASES (MLCK) --> CONTRACTION. DIALATE BY NO DIFFUSE ACROSS MEM TO SMOOTH MUSCLE CELL --> SOL GUAN CYCLASE --> cGMP INC PKG --> INH Ca INFLUX --> THEN REVERSED BY PDE (esp PDE5)

    • NEURONAL:
    • CNS (NEUROTRANS), PNS (SPHINC RELAX), SKEL MUSCLE (MOD CONTRAC FORCE). PRODUCED IN POST-SYNAP NEURON AND DIFFUSES BACK. SOL GUAN CYCLASE ACTIVATED BY NO --> cGMP --> GLUT & NOR SYNTH. PNS MYENTERIC, CARIAC, URO NO ACTIVATES SOL GUAN CYC WHICH RELAXES SMOOTH MUSCLE. SKEL RELAXED SIMILARLY.

    • INDUCIBLE NOS:
    • MACROs, NEUTROPHILS, LIVER. (NANOMOLAR). TRANSCRIPTIONAL VIA CYTOKINE OR ENDOTOXIN INDUCTION. CaM BOUND TO iNOS IN BASAL CONDITIONS SO IS ALWAYS IN ACTIVATED STATE. CYTOTOXICITY BY PEROXYNITRITE FORMATION, DNA CLEAVAGE AND DEAMINATION, NITROSATION OF PROTS, AND INH OF HEME PROTS.
  87. NO INVOLVEMENT IN SEPTIC SHOCK
    OVERPRODUCTION BY iNOS
  88. MECH OF ACTION OF SILDENAFIL (VIAGRA)
    ERECTION PROD BY NO-MEDIATED GENERATION OF cGMP --> VASODILATION VIA PKG. cGMP REMAIN ELEVATED

    cGMP DESTROYED BY PDE5 --> VIAGRA BINDS COMPETITIVELY TO cGMP THUS BLOCKING PDE5.

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