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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



Pyradoxal phosphate (PLP)

Derivative of vit B6- active site of amino transferases

alanine aminotransferase

alanine + alpha ketoglutarate --> pyruvate + glutamate




needs pyridoxal phostphate (PLP, vit B6) coenzyme

aspartate aminotransferase

aspartate + alpha ketoglutarate --> oxaloacetate + glutamate




needs pyridoxal phostphate (vit B6) coenzyme

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

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

Alkaptonuria

- No homogentisate oxidase: involved in degrading tyrosine


- Homogentisate accumulates --> dark urine, accumulation in joints --> arthritis

Homocystinuria

- defect in cystathionine beta-synthase: homocysteine --> cystathionine in catabolism of methionine


- Osteoporosis, CVD, mental retardation


- Can be caused by folic acid deficiency

stucture of urea

carboxyl oxygen with two amino groups attached

5 important enzymes of urea cycle

1. Carbamoyl phosphate synthetase I (CPS I)


2. Ornithine transcarboxylase


3. Argininosuccinate synthase


4. Argininosuccinate lyase


5. Arginase

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

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)

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

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

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)

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

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

Tyrosine hydroxylase

- Tyrosine + tetrahydrobopterin--> DOPA


- DOPA --> melanin


- DOPA + PLP --> nnorepinephrine --> epiniephrine

What can tryptophan be broken down to?

- Tryptophan + tetrahydrobiopterin --> --> serotonin


- serotonin: smooth uscle ocntraction, pain perception, behavior

What is histadine broken down to? what enzyme does it?

- hystadine decarboxylase: histadine + PLP --> Histamine + CO2


- chemical messenger for infalmmation, neurotransmitor, acid secretion

What is glutamate broken down to? what enzyme?

- glutamate decarboxylase: glutamate + PLP --> GABA + CO2


- GABA = inhibitory transmitter vs. glutamate as excitatory

What does arginine bet broken down into? what enzyme?

- NO synthase: L-Arginine + O2 ==> citralline + NO


- NO = neurotransmitter, immune fxn, smooth muscle relaxation

What processes require folate?

Amino acid synthesis (methionine and SAM)


Purine synthesis


Thymidine synthesis (DNA replication)

Dihydrofolate reductase

Folic acid--> Tetrahydrofolate




Target of chemo drugs

What enzyme transfers carbon from serine to THF in 1C metabolism?

Serine hydroxymethyl transferase: serine +THF --> N5N10-methylene-THF + glycine

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

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

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

What are the purine vs pyrimidine free bases?

Purine: Adenine, Guanine, Hypoxanthine (guanine -amino group)


Pyrimidines: Thymidine, Cytosine, Uracil

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

How do you make PRPP?

- PRPP synthase: Ribose-5-phosphate + ATP --> PRPP +ADP


- Inhibited by AMP/GMP/IMP

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

What is the product of purine de novo synthesis?

Inosine-mono-phosphate (IMP)

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

How do we breakdown excess purine bases?

- Xanthine oxidase: hypoxanthine --> xanthine --> uric acid (two reactions)


- Secrete uric acid in urine

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

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

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



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

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

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)

How make di and triphospho nucleotides?

- Nucleoside monophosphate kinases : XMP + ATP --> XDP + ADP


- Nucleoside diphosphate kinase: XDP + ATP --> ATP + ADP


-

How do you make CTP?

Cystosine triphosphate synthetase: UTP + glutamine + ATP --> CTP + Glutamate + ADP + Pi


(UTP from de novo pyrmidine pathway)

What enzymes do pyrimidine salvage?

Pyrimidine phosphoribosyl transferases: pyrimidine + PRPP --> mononucleotide pyrimidines

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

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

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

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



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

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

Mechanism of trimethoprim? when use?

Trimethoprim = DHF analog- competitively inhibits DHFR in microorganisms (not humans)




Part of cocktail treatment for strep, staph, malaria

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)

Mechanism of 6-mercaptopurine (purine analog)?

Scavenged like purine --> looks like purine levels high --> inhibits de novo synthesis of purines --> limits growth




cancer drug

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

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



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).

Mechanism Azidothymidine (AZT) (thymidine analog)

- Transported into cells, phosphorylated --> selectively inhibits HIV-DNA polymerase

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.



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.

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

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

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

Classifying proteases by substrate specificity

Cleaves after what kind of aa?


Positively charged aa


Negatively charged aa


Hydrophobic aa

Classifying proteases by cleavage location

Aminopepsidase: start at amino end work down


Endopepsidases: start wherever


Carboxypepsidases: start at carboxyl and work up

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

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

3 systems of protein degradation

1. Endosome-lysosome pathway


2. Extracellular proteases


3. Ubiquitin-directed

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)

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

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

CINH deficiency

No inhibitor of C1 in complement cascade --> uncontroled complement sx degrading cells --> angioedema and anaphylaxis

Anti-thrombin deficiency

No antithrombin, which inactivates thrombin which makes fibrin from fibrinogen in clotting. Unregulated clotting throughout body --> DVTs, PEs, miscarriages.

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

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

HPV and protein degradation

E6 viral oncoprotein: causes ubiquitination of p53 tumor suppressor protein --> cancer