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75 Cards in this Set
- Front
- Back
mTOR kinase |
- Off in starvation/protein deficiency --> induces autophagy - On with insulin activation after meal (Akt) --> inhibits autophagy |
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Pyradoxal phosphate (PLP) |
Derivative of vit B6- active site of amino transferases |
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alanine aminotransferase |
alanine + alpha ketoglutarate --> pyruvate + glutamate needs pyridoxal phostphate (PLP, vit B6) coenzyme |
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aspartate aminotransferase |
aspartate + alpha ketoglutarate --> oxaloacetate + glutamate needs pyridoxal phostphate (vit B6) coenzyme |
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glutamate dehydrogenase: where? what regulates? when active? |
glutamate --> alpha KG + ammonia - Liver, mito matrix - where excess nitogen shuttled after protein rich meal - reversible- depends on concentrations - ATP/GTP inhibit, ADP/GDP activate - Ammonia goes to renal excretion or urea cycle |
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Maple syrup urine disease |
- No alpha-keto-acid dehydrogenase: can't do the next step after aminotransferase in break down of isoleucine, leucine, valine - Build up of these aas and their ketoacids - Neuro defects and smell in urine, fatal - Treatment: low branch aa diet |
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Alkaptonuria |
- No homogentisate oxidase: involved in degrading tyrosine - Homogentisate accumulates --> dark urine, accumulation in joints --> arthritis |
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Homocystinuria |
- defect in cystathionine beta-synthase: homocysteine --> cystathionine in catabolism of methionine - Osteoporosis, CVD, mental retardation - Can be caused by folic acid deficiency |
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stucture of urea |
carboxyl oxygen with two amino groups attached |
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5 important enzymes of urea cycle |
1. Carbamoyl phosphate synthetase I (CPS I) 2. Ornithine transcarboxylase 3. Argininosuccinate synthase 4. Argininosuccinate lyase 5. Arginase |
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N-acetylglutamate synthase: |
acetyl CoA + glutamate --> N-acetylglutamate + CoA - Activated by arginine - N-acetyl gluatmate activates CPS I - THUS when arginine high after high protein meal --> high urea cycle activity |
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Short and long term regulation of urea cycle |
Short: - Substrate concentrations - N-acetylglutamate activates CPS1 Long: - extended high protein diet: Up regulation of urea cycle enzymes - Insulin down regulate enzymes - Glucagon upregulates enzymes (starvation signals) |
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How use glutamine as ammonia transport? |
- Glutamine synthase: glutamate + NH3 --> glutamine in muscle cells --> glutamine transport through blood. - Glutaminase: glutamine --> glutamate + NH3 in liver --> NH3 into urea cycle |
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Glucose-Alanine cycle |
- In muscle: pyruvate from glycolysis, glutamate from aa break down --> pyruvate + glumate = alanine --> alanine to liver - In liver: alanine + alphaKG --> glutamate and pyruvate --> pyruvate into gluconeogen and glutamate into NH3 via glutamate dehydrogenase --> NH3 into urea cycle |
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Ornathine transcarboxylase deficiency |
- Most common urea cycle issue---> hyperammonemia - Early/ late onset based on severity - lethargy, vomiting, seizures, etc. - Treatment: low protein intake (not that effective), arginine (drive pathway to make citrilline), lactulose(inhibit NH3 absorption in gut), liver transplant (best) |
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Phenylketonuria (PKU) |
- Hyperphenylalanemia - No phenylalanine hydroxylase: phenylalanine --> tyrosine with help of tetrabiopterin - accumulated phenylalanine--> phenylpyruvate (ketone) --> phenyllacetate (disrupts tyrosine pathway) - Issues due to low tyrosine, which makes melanin and catecholamines and other important stuff - Seizures, mental retardation, failure to grow, hypopigmentation - Treatment: synthetic diet low in phenylalanine, supplemented with tyrosine |
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What happens if defective dihydrobiopterin reductase (DHFR)? |
- No conversion of dihydrobiopterin to tetrahydrobiopterin - Hyperphenylalanemia, accumulation of tyrosine and tryptophan too - Tyrosine --> DOPA --> melanin, catecholamines, tissue proteins, fumerate/acetoacetate - Tryptophan --> serotonin - Treatment: synthetic diet, replace biopterin, DOPA etc |
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Tyrosine hydroxylase |
- Tyrosine + tetrahydrobopterin--> DOPA - DOPA --> melanin - DOPA + PLP --> nnorepinephrine --> epiniephrine |
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What can tryptophan be broken down to? |
- Tryptophan + tetrahydrobiopterin --> --> serotonin - serotonin: smooth uscle ocntraction, pain perception, behavior |
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What is histadine broken down to? what enzyme does it? |
- hystadine decarboxylase: histadine + PLP --> Histamine + CO2 - chemical messenger for infalmmation, neurotransmitor, acid secretion |
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What is glutamate broken down to? what enzyme? |
- glutamate decarboxylase: glutamate + PLP --> GABA + CO2 - GABA = inhibitory transmitter vs. glutamate as excitatory |
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What does arginine bet broken down into? what enzyme? |
- NO synthase: L-Arginine + O2 ==> citralline + NO - NO = neurotransmitter, immune fxn, smooth muscle relaxation |
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What processes require folate? |
Amino acid synthesis (methionine and SAM) Purine synthesis Thymidine synthesis (DNA replication) |
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Dihydrofolate reductase |
Folic acid--> Tetrahydrofolate Target of chemo drugs |
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What enzyme transfers carbon from serine to THF in 1C metabolism? |
Serine hydroxymethyl transferase: serine +THF --> N5N10-methylene-THF + glycine |
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What 3 enzymes are involved in transfering 1C from serine to methionine? |
1. Serine hydroxymethyl transferase: serine +THF --> N5N10-methylene-THF + glycine 2. N5N10- methylene-THF reductase: N5N10- methylene-THF --> N5-methyl-THF 3. Homocysteine methyl transferase: N5-methyl-THF + homocysteine +B12 --> methionine |
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What intermediates accumulate with B12 deficiency? Effect? Sx? |
- Homocysteine and N5-methyl-THF accumulate --> makes it unfavorable to make THF intermediates from serine/histadine/formate --> all processes that depend on folate suspended. -Neural tube defects in fetus- not enough precursors for DNA synth and replication in neurons - Megaloblastic anemia: not enough DNA synth substrates for making RBCs from stem cells |
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How make SAM from methionine? what can SAM do? |
- S-Adenosylmethionine synthase: methionine +ATP --> SAM and THF - Methylation of phospholipids, norepi and epi, creatinine and carnitine synthesis |
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What are the purine vs pyrimidine free bases? |
Purine: Adenine, Guanine, Hypoxanthine (guanine -amino group) Pyrimidines: Thymidine, Cytosine, Uracil |
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What enzyme is the first committed step in de novo purine synthesis? |
- Glutamine: phosphoribosyl pyrophosphate amidotransferase:: Glutamine + PRPP --> 5-phosphoribosylamine + Glutamate - Adds amino group to ribose derivative that nucleotide base will build from - Activated by PRPP (allosterically) - Inhibited by AMP/IMP/GMP |
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How do you make PRPP? |
- PRPP synthase: Ribose-5-phosphate + ATP --> PRPP +ADP - Inhibited by AMP/GMP/IMP |
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What regulates synthesis of AMP/GMP from IMP? |
- IMP to AMP is inhibited by AMP - IMP to GMP is inhibited by GMP - keeps balance of purine concentrations |
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What is the product of purine de novo synthesis? |
Inosine-mono-phosphate (IMP) |
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What enzymes are important to the purine salvage pathway? When do we use salvage? |
- Hypoxanthine-guanine phosphoribosyl transferase (HGPT): hypoxanthine/guanine + PRPP --> IMP/GMP + PPi - Adenine phosphoribosyl transferase (APRT): adenine + PRPP --> AMP + PPi - Bases from diet/ cell turnover |
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How do we breakdown excess purine bases? |
- Xanthine oxidase: hypoxanthine --> xanthine --> uric acid (two reactions) - Secrete uric acid in urine |
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Lesch-Nyan Syndrome |
- Deficiency in HGPRT (salvage pathway) --> build up of PRPP --> drives de novo pathway --> too many purine bases --> drives break down into uric acid --> hyperuricemia --> gout - Sx: mental retardation, self harm - Treatment: allopurinol, restraints |
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What causes hyperuricemia? who gets gout? |
- Over secretion of uric acid: Lesh-Nyan, gain of function in PRPP (rare) - Under excretion of uric acid: kidney function compromised, anion transporter mutation (more common) - Only 20% of people with hyperuricemia get gout- some people immune sx attacks crystals and some dont |
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Gout: sx? mechanism? risk factors? how dx? |
- Sx: severe pain/redness in joints of feet - Mech: hyperuricemia --> deposit crystals on worn joints in feet --> immune sx attacks crystals --> inflammation and pain - Risk factors: obesity (kidney stress), diet (pork,beef, lamb, soft-drinks, alcohol) - Dx: take fluid sample from joint and observe crystals under microscope |
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How treat gout? |
- Allopurinol: Xanthase oxidase inhibitor --> accumulation of purines inhibits de novo synth. Also hypoxanthine/ guanine to go down alternate, benign excretion pathway - Cochicine: for acute attack, prevents microtubule growth needed for neutrophil migration |
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What components go into making de novo pyrimidine bases? What is end product? |
- Aspartate, glutamine, CO2 (doesnt require folate) - Make base and add PRPP later - End: UMP |
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What is first, committing step of de novo pyrimidine synthesis? what regulates? |
- Carbamoyl phosphate synthetase II (CPSII): Glutamine + CO2 + ATP --> carbamoyl phosphate + glutamate - Inhibited by UTP - Activated by ATP and PRPP (keep balance) |
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How make di and triphospho nucleotides? |
- Nucleoside monophosphate kinases : XMP + ATP --> XDP + ADP - Nucleoside diphosphate kinase: XDP + ATP --> ATP + ADP - |
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How do you make CTP? |
Cystosine triphosphate synthetase: UTP + glutamine + ATP --> CTP + Glutamate + ADP + Pi (UTP from de novo pyrmidine pathway) |
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What enzymes do pyrimidine salvage? |
Pyrimidine phosphoribosyl transferases: pyrimidine + PRPP --> mononucleotide pyrimidines |
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How make deoxy version of nucleotides for DNA synthesis? How regulated |
- Ribonucleotide reductases: NDP + Thioredoxin (SH-SH) --> dNDP + Thioredoxin (S-S) + H2O - Specificity determined by what ribonucleotides are around --> balance - Inhibited by dATP |
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Adenosine Deaminase (ADA) Deficiency |
- Adenosine deaminase: adenosine + H2O --> inosine + NH3, usually active when too much AMP. AMP --> inosine --> hypoxanthine for excretion via uric acid - ADA deficiency: build up AMP --> salvage pathways take up --> dATP level rises --> inhibits ribonucleotide reductases --> low levels of dNTPS --> poor cell division - Sx: SCID: lack of B and T cells (require lots of dNTPs for rapid division of immune cells) - Tx: bone marrow, ADA supplementation |
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How make thymidylate (dTMP)? |
- Thymidylate synthase: dUMP + N5N10-methylene-THF --> dTMP + DHF - folate dependent (need DHFR too) - highly expressed in fast growing cells - target of chemo drugs |
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What enzyme targeted by sulfa drug anti-biotics? |
- Dihydropteroate synthase: synthesizes folic acid in microorgainisms. Humans don't have. - Inhibit growth of bacteria but does not kill it |
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What is mechanism of methotrexate? |
- Chemo drug - Folic acid analong- transporter via folic acid transport - Competitively inhibits DHFR (binds tight) --> no THF needed for growth of fast growth cells - Often use in high dose to kill off lots of cells and then rescue with intro of thymidine, hypoxanthine, methionine - Also targets hair follicles, GI, immune cells |
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Methotrexate resistance- mechanisms? what makes cells able to resist? |
- Decrease [methotrexate] in cell: down-regulate folic acid transporter - Decrease effectiveness of drug: mutation makes it less competitive at binding DHFR, increase DHFR activity |
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Mechanism of trimethoprim? when use? |
Trimethoprim = DHF analog- competitively inhibits DHFR in microorganisms (not humans) Part of cocktail treatment for strep, staph, malaria |
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What is the mechanism of fluorouracil (uracil analong)? when used? |
Salvaged like uracil, made into F-dUMP, inhibits thymidylate synthase by wreking active site of enzyme --> no dTMP pools --> inhibit cell growth (chemo drug) |
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Mechanism of 6-mercaptopurine (purine analog)? |
Scavenged like purine --> looks like purine levels high --> inhibits de novo synthesis of purines --> limits growth cancer drug |
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Mechanism of allopuranol? |
- Hypoxanthine analog: xanthine oxidase makes it into a compound that clogs xanthine oxidase --> decrease uric acid levels AND causes increase in purine bases that inhbits denovo synthesis of purines - Treats gout |
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Mechanism of AraC (deoxycytosiene analog)? |
- Salvaged like dCMP, deoxycytodine kinase makes it dCTP--> polymerases add to nucleotide chain and then can't add another --> chain termination |
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Mechanism of acyclovir (thymidylate analog)? Treats what? |
- Viral deoxythymidine kinases convert to deoxytriphosphate form --> substrate for viral DNA opol --> causes chain termination - Treat herpes. Selects for virally infected cells (have viral thymidine kinases). |
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Mechanism Azidothymidine (AZT) (thymidine analog) |
- Transported into cells, phosphorylated --> selectively inhibits HIV-DNA polymerase |
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Cyclin-- what kind of protein degradation does it illustrate? |
Illustrate protein degradation for removing regulatory proteins Cyclin made constitutively- prevents propagation of mitosis. Targeted by ubituitin and broken down at cell check-point --> mitosis moves forward. |
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Cystic fibrosis- how related to protein degradation? |
Illustrates protein degradation for quality control. Gene mutation to Cl transport protein. The transporter is actually still functional, but recognized as wrongly folded and thus degraded --> pts lack Cl transporter. |
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Alcohol liver damage - how related to protein degradation? |
Illustrates degradation of damaged proteins Toxic metabolites damage liver proteins, back up in the liver protein breakdown sx because maxed out--> mallory bodies of damaged protein |
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How does the immune sx use protein degradation? |
- Use ubiquitin to breakdown intracellular proteins and present on MHC I for CD8 cells - Use lysosomal protein breakdown sx to sample extracellular environment --> break proteins down --> present peptides on MHC II |
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Classifying proteases by nucleophile |
- Serine: common, has hydroxyl group that attacks carboxyl of peptide bond - Cysteine: lysosomeal proteases - Threonine: proteasome proteases Only - Water: metalloproteases and acid proteases |
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Classifying proteases by substrate specificity |
Cleaves after what kind of aa? Positively charged aa Negatively charged aa Hydrophobic aa |
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Classifying proteases by cleavage location |
Aminopepsidase: start at amino end work down Endopepsidases: start wherever Carboxypepsidases: start at carboxyl and work up |
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If breaking a peptide bond is energetically favorable, why does it require ATP to break down proteins? |
Energy to control process so dont have non-specific protein degradation |
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4 mechanisms to control protein breakdown |
1. Natural inhibitors: proteins made along with protease that inhibit the protease. Eg: serpins for serine proteases 2. Zymogens: inactive pre-proteins, require cleavage to be active -- cascade 3. Compartments: separate proteases from harming rest of cell 4. Death signals: use tags like ubiquitin to direct proteases to what should be destroyed |
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3 systems of protein degradation |
1. Endosome-lysosome pathway 2. Extracellular proteases 3. Ubiquitin-directed |
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2 kinds of endosome-lysosome degradation and how regulated |
1. Endocytosis 2. Autophagy: upregulated by starvation signals like TNF - lysosomal proteases: cathepsins - control via membrane, low pH adaptation, cystatins (natural inhibitors in cytoplasms) |
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What processes require extracellular proteases? |
- Pancreatic proteases: trypsin - Thromin cascade: throbin converts fibrinogen --> fibrin --> clotting - Complement cascade - Matrix metalloproteases/elastase: tissue remodeling - Plasmin cascade: flibroginolysis, clot break down |
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alpha1-antitrypsin deficiency |
- Lack anti-trypsin, which is suicide substrate for proteases --> shuts them down - Proteases opperate unchecked --> breakdown lung tissue --> emphysema. Misfolded anti-trypsin builds up in liver -> liver failure |
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CINH deficiency |
No inhibitor of C1 in complement cascade --> uncontroled complement sx degrading cells --> angioedema and anaphylaxis |
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Anti-thrombin deficiency |
No antithrombin, which inactivates thrombin which makes fibrin from fibrinogen in clotting. Unregulated clotting throughout body --> DVTs, PEs, miscarriages. |
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Ubiquitin conjugation |
- E1 (ubiquitin activating enzyme): binds to ubiquitin making thioester bond. There is one kind of E1 everywhere - E2/E2 (ubiquitin ligase): many kinds, combo determines specificity of protein binding. - Ub transfered from E1 to E2, protein with death signal bound specifically --> Ub binds amine on protein --> isopeptide bond--> subsequent Ubs attach to first one via E1 |
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The proteasome: what is it made of? what does it require? |
Proteases (all threonine, different specificities) stacked in cyclindrical core. - Requires ATP to unwind protein - Isopepsidase specific for Ub isopeptide bond |
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HPV and protein degradation |
E6 viral oncoprotein: causes ubiquitination of p53 tumor suppressor protein --> cancer |