Biochemistry - Unit III - Neurobiochemistry, Oncology, DNA repair

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  1. Major metabolic pathways in the brain
    • in the absorptive state
    • glucose-GLUT-1->glucose-glycolysis->acetyl CoA->TCA->ATP+CO2+H2O
    • during fasting
    • ketobodies->acetyl CoA->...
  2. GLUT-1 is insulin _______
  3. The depolarization phase of an action potential is due to ___________; The repolarization phase of an action potential is due to ___________.
    • the opening of voltage-gated sodium channels
    • the opening of voltage-gated potassium channels
  4. Local anesthetics block __________.
    • voltage-gated sodium channels
    • all contain tertiary amine, which contains a positive charge under physiological pH and is involved in blocking the Na chan
  5. Sequential activation of gated ion channels at a neuromuscular junction
    • AP at motor neuron -> voltage-gated Ca2+ chan open and Ca2+ influx -> ACh released -> ligand-gated nicotinic receptor (ionotropic) > Na+ influx, K+ efflux -> voltage-gated Na chan open -> depolarization -> Ca2+ released from ER (SR) -> contraction
    • endocrine cells use similar mechanism
    • Nicotine is more effective at brain
  6. parasympathetic system causes reduced muscle contraction via:
    • muscarinic AChR (GPCR) -> G binds to GTP and Gβγ binds to K chan -> K chan opens and outflow -> hyperpolarize
    • epinephrine has the opposite effect
  7. bacterial toxin
    • cholera toxin -> prolonged activation of GsPCR -> continuous activation -> severe diarrhea
    • pertussis toxin -> prolonged inactivation of GiPCR -> disable the inhibition -> whooping cough
  8. Parkinson disease
    • •  Common neurological disorder in US
    • •  Symptoms: paucity of spontaneous movement, tremor at rest, muscle rigidity, shuffling gait, mask-like facial expression, autonomic disturbances, depression, cognitive impairment
    • •  Results from degeneration of dopamine neurons in the substantia nigra pars compacta
    • •  Oral administration of L-DOPA was found beneficial but effects diminish >5 years (do not administer dopamine directly because it does not cross BBB; L-DOPA transporter exists)
  9. Benzodiazepines facilitate ______ transmission
    • GABAergic
    • used as anti-axiety and anesthetic
    • GABA: major inhibitory neural transmitter
    • At high doses, anti anxious -> unconscious
    • rape drugs
  10. Opiate analgesics: exert their activity by binding
    • to ____ receptors in brain, which are ____.
    • opioid
    • GPCRs
  11. inappropriate proteolytic cleavage of ___________ can lead to Alzheimer disease
    • amyloid precursor protein (APP)
    • normally degraded by α- and γ-secretase
    • in Alzheimer, β-secretase cleaves the protein into longer-than-normal amyloid, Aβ42, which tends to aggregate and form amyloid plaque
  12. Energy production in cancer cells is characterized by:
    • aerobic glycolysis: the Warburg effect
    • behave like normal cells in anaerobic environment, pyruvate is mostly converted to lactate and provides very little ATP compared to TCA.
  13. Development of Cancer Requires ___________
    • Several Mutations: the multi-hit model
    • 5-6 hits before malignant cancer cells emerge
  14. There is a strong relationship between the lifetime risk of cancer in a given tissue and ______________.
    the number of stem cell divisions in the lifetime of that tissue
  15. Classes of genes implicated in the onset of cancer
    • Proto-oncogene - dominant; Ras
    • Tumor-suppressor gene - recessive; p53
    • Caretaker genes - DNA repair
  16. Ras active - inactive transformation
    • inactive form binds to GDP
    • under the help of GEF (G exchange factor), it releases GDP and GTP, which has higher concentration than GDP, binds to it
    • becomes the active form
    • the GTPase function of Ras tends to convert GTP to GDP, there are signals promote or inhibit the conversion
    • Ras becomes inactive again
    • The oncogenic mutation of RasV12 loses the GTPase function, thus becomes permanently active
  17. Ras/MAPK pathway
    • active Ras activates Raf
    • active Raf activates MEK
    • active MEK activates MAPK
    • active MAPK translocates to nucleus and activates many transcription factors
  18. The development of human cancer
    has a defined development from benign tumor to metastasis (migrating), including accumulation of mutations
  19. Effects of oncogenic mutations in proto-oncogenes that encode cell-surface receptors
    after mutation the receptor becomes ligand-independent, constantly active kinase
  20. chronic myelogenous leukemia (CML)
    • translocation of chromosomes
    • fusion Bcr-Abl protein Tyr kinase
    • inhibitor, Imatinib (Gleevec), developed to specifically block the Tyr kinase and used to treat CML and some other cancers
  21. p53 is a tumor suppressor and mutations of p53 are prevalent (>50%) in many cancers
    • activated in response to DNA damage
    • leads to apoptosis, G1 and G2 arrest, and DNA repair
    • mutation -> cancer
  22. Damage to DNA is unavoidable and arises in many ways:
    • Spontaneous cleavage of chemical bonds in DNA
    • Environmental agents: uv and ionizing radiation
    • By-products of normal cell metabolism: reactive O2 species
    • Environmental genotoxins
    • Mistakes during DNA replication or repair
    • Defects in DNA repair mechanisms and cancer are closely related
  23. Point mutations in mRNA
    • nonsense mutation: becomes a stop codon
    • missense mutation: becomes codon of a different AA
    • silent mutation: corresponds to the same AA, no effect
  24. point mutation: transition vs transversion
    • transition: purine->purine or pyrimidine->pyrimidine
    • transversion: purine<->pyrimidine
  25. ____ is usually considered to be the mutated base when there is a mismatch
    • T
    • spontaneous deamination: Met-C -> T
  26. Base excision repair of a T-G mismatch
    • DNA glycosylase cleaves the glycosidic bond between the base and the sugar, removes the thymine and leaves behind the deoxyribose
    • APEI (Apyrimidinic) endonuclease creates a nick
    • Lyase cleaves off the sugar
    • DNA Pol β fills in the gap
    • DNA ligase forms the phosphodiester bond
    • Oxidized bases can also be removed through this process
  27. Mismatch excision repair
    • some machinery recognize the mismatch
    • an endonuclease makes a nick
    • helicase and exonuclease together remove a segment around the error
    • polymerase and ligase together fill the gap
    • mutation of the recognizing machinery or the endonuclease -> hereditary nonpolyposis colorectal cancer (HNPCC)
  28. Nucleotide excision repair
    • adjacent T form cyclobutane w/ UV radiation
    • many proteins involved in the repair, including TFIIH, which is also a transcription factor and has helicase function
    • recognize->helicase+endonuclease-> segment with error removed -> polymerase and ligase repair the gap
    • mutation of involved proteins genes resulted in xeroderma pigmentosum
  29. Error-prone repair by nonhomologous end-joining
    • when double strand breaks
    • DNA-PK, KU70/KU80 dimer, and other proteins cleave short the broken ends and attach them together directly
    • the new DNA is shorter than the original, last resort of DNA repair
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Biochemistry - Unit III - Neurobiochemistry, Oncology, DNA repair
2016-03-15 22:57:54
Biochemistry - Unit III - Neurobiochemistry, Oncology, DNA repair
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