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Diisopropyl Phosphofluridate
- irreversible acetylcholinesterase
- overactivation of the parasympatheic pathway
- similar to organo-phosphate poisioning
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Allopurinol
- Xanithine Oxidase inhibitor
- Prevent the breakdown of hypoxanthine to Urate
- Allievation of gout/uric acid poisoning
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Malonic Acid
- Competitive inhibitor of succinate dehydrogenase
- displacing succinic acid
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Ethanol
competitive inhibitor of alcohol dehydrogenase for methanol
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Fomepizole
- competitive inhibitor of alcohol dehydrogenase
- used for methanol and ethanol poisoning
- does not produce formaldehyde products which are poisonous to occular nerve
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Ki of competitive inhibitors
- the lower the Ki(Km of inhibitor) compared to the Km of the original (k-1/k1) substrate the more competitive the drug is for the inhibition of the ES complex
- instead forms EI complex
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Competitive vs none competitive inhibition
Km change in competitive and Vmax change in none competitive
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Homotropic allosteric effectors
- substrate binding changes the enzyme kinetics
- hemoglobin binding to oxygen is considered homotropic
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Lysozomal Peptidoglycan hydrolysis
- breaks NAM-NAG repeats in bacterial wall
- lysis of glycosidic bonds (2 sugars in this case)
- Glutamate and Aspartate catalytic peptides
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Chymotrypsin
- Serine-protease (serine lead bond breaking)
- his, asp, ser catalytic triad
- break down peptide bonds
- trypsin and elastase in the same family
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Carbonic anhydrase
- H2O+CO2<--> H2CO3
- bicarbonate buffer system
- binds metals
- conversion of CO2 to carbonic acid (intermediate)
- inhibitor Acetazolamide can treat glacoma and respiratory alkidosis by increasing CO2 levels in body
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HMG-CoA Reductase
- Cholesterol biosynthesis
- end stage of beta hydroxylation
- over production of cholesteral in familial hypercholesterolemia
- Inhibitor of statin
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Acetylcholinesterase
- gets ride of your aceytlchoine into choline and acetate with water
- inhibitors are poisons (organophosphates fasciculin-II, diisopropyl phosphofluridate)
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G1 Check point
- Cyclin D+ CDK4/6 act.
- Cyclin E+ CDK2 act
- S - phase
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G2 Check point
- Cdc25 act
- CDK1
- Cyclin A+CDK1 act
- Cyclin B
- Cyclin B + CDK1 act
- Mitosis Promoting Factor
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Metaphase - Anaphase check point
- Sister chromatid seperation using seperase
- Cdc20 act
- APC tagging
- securin for ubiquitinalytion
- seperase free to cut cohesin
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Phosphofructokinase-1
- PFK1 phosphorolates fructose 6-phosphate
- committs sugar to glycolytic pathway
- add the 2nd ATP to the sugar molecue
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hexokinase (glucokinase)
- adds first ATP to sugar
- hexos version does all sugars with low Km
- Gluco version in liver is only for glucose and has high Km compared to hexos, will not be saturated and only kicks in when there is EXCESS glucose
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Glyceraldehyde 3-phosphate DH
- Adds 1 PiH to each of the two glyceraldehyde 3-phosphate WITHOUT using ATP
- produces 1,3 bisphospholycerate
- NAD+ is reduced to NADH
- NADH is used eithe rin oxidative phosphorylation or anarobic respiration of pryruvate to lactic acid
- 3rd and last Pi addition to sugar substrate
- now you have 2 bisphosphates each with 2 Pi's
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Phosphoglycerate Kinase
- PGK - produces the first ATP of glycolysis
- taking the Pi that we just put on with GAPDH
- first pay off
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Pyruvate kinase
2nd and last substrate level phosphorylation (not linked to eletrcon transport chain)
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Glycolysis Net
- 2ATP (added 4Pi but only 2 cost ATPs and took off 4Pi)
- 2NADH
- 2 pyruvate
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Cori Cycle
- Gluconeogensis at liver
- makes glucose from lactate
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Glycolysis regulation
- PFK-1 negativly regulated by ATP allocsticly
- increases Km while not affecting Vmax
- AMP lowers Km
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ATP/AMP regulation
- negative for PFK and PK - ATP
- pos for PFK and PK - AMP
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None glycolysis substrate regulation of glycolysis
- F2,6BP regulates PFK-1 by reducing its Km
- insulin/glucogon --> phosphorylation of PFK-2 --> phosphorylates F6P to F2,6BP(not a part of glycolysis) --> decreases Km for PFK-1
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High NADH
- Results from alcohol metabolism
- inhibits citric acid cycle, gluconeogensis and fatty acid oxidation
- promotes fatty acid synthesis in liver
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Ethanol Metabolism
- Alcohol dehydrogenase
- aldehyde dehydrogenase
- produce high energy NADH and acetate
- drive motabosim towards ketone bodies and fatty acids
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PKA and cAMP in Glycolysis
in liver and adipose cells
- Control molecues
- ↓insulin ↑cAMP ↑PKA↑PFK-2 activity ↓F2,6BP↓PFK-1 activity ↓ glycolysis
vise versa
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PKA/PFK-2 in cardiac muscle
similar ↑ cAMP will ↑PKA BUUUT ↑ PFK-2 KINASE activity ↑F2,6BP ↑PFK-1
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PFK-2
- PKA phosphorylation to change activity
- phosphorylate --> phosphatase in liver cells
- phosphorylate --> kinase in cardiac muscles
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Pyruvate Kinase Regulation
- ↑ATP/Ala ↓ PK
- ↑PEP ↑PK
- ↑F-1,6,P2 ↑PK
- ↑cAMP ↑PKA ↓PK -similar to liver glycolysis to conserve glucose during fasting or energy need
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Hemolytic anemia
hexokinase deficiency in erythrocyte
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Pyruvate kinase deficiency
- hemolytic anemia, pallor, jaundice, ulcers
- due to hemolytic issues, enlarged speen, low RBC
- low ATP with elevated 2,3,BPG
- genetic disorder for isozyme of PK in RBC
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E2F
- grows
- inactive E2F-Rb form
- activated by CyclinD+Cdk4/6
- E2f free form produces Cyclin E
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Cyclin E
- promoted by free E2F
- with Cdk2 -> goes into S phase
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Cdc20
- chromatid stress produced
- activates APC
- with cdc14 dephosphorylate seperase to activate
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APC - cell regulation
- APC ubiquitinalytes securin
- releases seperase
- seperase still phosphorylated(inactive, needs Cdc 20/14)
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Seperase
- regulated by amount of Cdc20 through APC
- inactive bound to securin
- active cleave cohesin --> anaphase
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G2-M regulation
- Cdk 1 activity:
- activated by Cdc25 and deactivated by WEE-1
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Mitosis promoting factor
- Cdk-1 + Cyclin B
- Cdk activation by Cdc25
- Cyclin B activation by Cdk1+Cyclin A
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p53
- p53 kills (tumor necrosis factor)
- inactive if bound to mdm2
- alone it promots apoptosis
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Alcohol Metabolism
- Alcohol dehydrogenase (requires NAD+)
- --> acetal-adyhyde
- Acetalaldyhyde dehydrogenase
- -->acetic acid
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Alcohol inhibition of gluconeogenisis
- Alcohol degradation eats up NAD+ and pyruvate
- Both are needed for pyruvate carboxylase, rate limiting step of gluconeogenisis
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