Lecture 4 Flashcards
How are proteins stored?
No storage form of proteins. We get them from diet, make from scratch (de novo), and made from normal protein degradation.
Excess AAs are degraded. Not stored.
How to breakdown AAs?
1.) strip amino group away, making it vulnerable. A-keto acid is the remainder.
2.) amino group becomes ammonia.
3.) NH4+ either excreted in urine or converted to urea.
How does Nitrogen enter and leave the body?
Enters via food, leaves via urea, ammonia.
What happens in the stomach during digestion of dietary proteins?
HCl denatures protein and kills bacteria
Pepsin hydrolyzes proteins.
What happens in the small intestine during digestion of dietary proteins?
Pancreatic proteases cleave polypeptides
Aminopeptidases make smaller peptides / free AAs
Small peptides (typically 2, no more than 4 AAs)/ Free AAs taken up by enterocytes. Hydrolyzed in cytosol.
Transamination process, know pdts and enzymes
A - keto acid becomes a-amino acid after aminotransferase transfers an NH3. This NH3 gets transferred to a-ketoglutarate, which forms Glutamate.
Note* a-ketoglutarate is the most common nitrogen acceptor.
Deamination process
Reverse of transamination. Glutamate loses NH3 to form a—ketoglutarate via enzyme glutamate dehydrogenase. NH3 (ammonia) is released to liver.
Where is urea produced in the body, and what enzyme is the rate limiting step?
Urea produced in liver. Less toxic than ammonia.
Carbamoyl phosphate synTHEtase 1. (Requires atp).
Urea cycle, what is happening in what location of the cell?
1.) starts off in mitochondria. CO2 combines with ammonia and ATP to form carbamoyl phosphate via rate limiting step Carbamoyl phosphate synTHEtase I.
2.) L-ornitine comes from cytosol to mitochondria in order to react with carbamoyl phosphate to produce L-citrulline.
3.) L-citrulline transported to cytosol, reacts with L-aspartate.
4.) (skip some steps) L-arginine forms, forms L-ornithine and Urea via arginase enzyme.
Where do nitrogens/carbons come from to make urea?
1 nitrogen comes from ammonia (in mitochondria), other from L-Aspartate (in cytosol)
1 carbon comes from a CO2
Where is urea made and where does it go?
Made in liver, goes through blood and into kidney. Some urea goes to intestine, which then reacts with Bacterial Urease to make ammonia. Ammonia can go back into blood.
How does kidney failure affect the fate of urea?
Plasma urea levels elevate (due to urea going to intestine). Promotes transfer of urea from blood to gut. Contributes to hyperammonemia.
What are glucogenic AAs?
AAs whose catabolism yields pyruvate or one of intermediates in TCA cycle.
What are Ketogenic AAs?
AAs whose catabolism yields either acetoacetate or one of its precursers (acetyl CoA or acetacetyl CoA)
Different Disorders of AA metabolism and what they do?
Phenylketonuria: overaccumulation of phenylalanine. Deficiency in phenylalanine hydroxylase
Phenylalanine -> Tyrosine inhibited.
Albinism: lack of tyrosinase. Melanin not produced.
Tyrosine -> Melanin inhibited.
AAs are precursors to nitrogen containing compounds such as :
Porphyrins, Neurotransmitters, Hormones, Purines, Pyrimidines.
Most prevalent porphyrin is…
Heme
Major sites of heme biosynthesis
Liver, and erythrocyte-producing cells of the bone marrow.
Note* Mature red blood cells lack mitochondria and are unable to synthesize heme.
Important steps of Heme synthesis
1.)Glycine and succinyl Coa (precursors) react with enzymes ALAS1 and ALAS2
2.) New structure then reacts with omega-Aminolevulinic acid dehydratase. In cytosol. (Lead inhibits this one, which is why its important)
3.) Bunch of other stuff. Final enzyme is Ferrochelatase. In mitochondria. Heme produced.
Inhibitors to Heme synthesis
Heme inhibits ALAS1
LOW IRON inhibits ALAS2.
Lead inhibits omega-Aminolevulinic acid dehydratase
Lead inhibts Ferrochelatase too.
Note* Iron does not inhibit ALAS2, but low amounts do. Adequate Iron is an activator of ALAS2.
Lifespan of Heme, and where do RBCs get degraded?
After ~120 days circulation, RBCs degraded particularly in liver/spleen.
Degradation of Heme and enzymes.
1.) Heme -> Biliverdin via Heme oxygenase
2.) Biliverdin -> Bilirubin via Biliverdin reductase
3.) Bilirubin conjugated to an acid to make it more soluble to go into bile.
Note* Heme oxygenase is the main step in the body that produces carbon monoxide (CO).
Excessive amounts of bilirubin disease
Juandice (yellowing of eyes/skin)
Catecholamine synthesis
1.) Tyrosine (precursor) -> dopa (3,4-dihydroxy-phenylalanine) via Tyrosine hydroxylase.
2.) Dopa -> dopamine via PLP (pyridoxal phosphate, vitamin B6)
3.) Dopamine -> Norepinephrine
4.) Norepinephrine -> Epinephrine
Norepinephrine / epinephrine effects
Important Catecholamine disease
Regulate carbohydrate / lipid metabolism
Involved in fight or flight response.
Parkinson disease results from insufficient dopamine production
Degradation of Catecholamines
1.) Epinephrine / Norepinephrine degrades to VMA by COMT/MAO. Sequence doesnt matter.
COMT = methylating enzyme.
MAO = oxidase
SAM =methyl donor.
1.) Dopamine degrades to HVA by COMT/MAO. Sequence doesnt matter too.
Note* VMA and HVA are acids.
Precursor to Histamine
Histidine
Precursor to Serotonin
Tryptophan
Precursor to Creatine
Arginine, Glycine
What can creatine phosphate do?
Can provide a brief amount of energy (~1 min) by making ATP.
Gives phosphate to ADP -> ATP.
Muscle mass proportional to creatine phosphate in body.
Melanin synthesis
Tyrosine -> melanin via tyrosinase
Nucleotides are composed of…
Nitrogenous base, sugar phosphate. (Sugar phosphate = pentose monosaccharide, 1,2,3 phosphate groups.)
Nucleotides belong to 2 families: purines/pyrimidines.
DNA/RNA Purines
Adenine
Guanine
DNA Pyrimidines/RNA Pryimidines
Thymine Cytosine Uracil
Dif between Nucleoside and nucleotide
Nucleosides lack phosphate (compared to nucleotide)
Base Purine/Pyrimidine Names
Adenine
Guanine
Cytosine
Uracil
Thymine
Ribonucleoside names
Adenosine
Guanosine
Cytidine
Uridine
Ribonucleotide
Adenylate (AMP)
Guanylate (GMP)
Cytidylate (CMP)
Uridylate (UMP)
Deoxyribonucleoside Names
Deoxyadenosine
Deoxyguanosine
Deoxycytidine
Deoxyuridine
Deoxythymidine
Deoxyribonucleotide Names
Deoxyadenylate (dAMP)
Deoxyguanylate (dGMP)
Deoxycytidylate (dCMP)
Deoxyuridylate (dUMP)
Deoxythymidylate (dTMP)
Synthesis of Purines
1.)Ribose-5-phosphate -> PRPP via PRPP synTHEtase (require ATP)
2.) PRPP + Glutamine, Glycine, Aspartate = IMP
3.) IMP -> dGMP/ dAMP via Ribonucleotide reductase.
Note* Ribonucleotide reductase deoxifies nucleotide.AMP and GMP converted to deoxy form by this enzyme.
Salvage pathways for purines, and where is it important in body?
Important in brain, bc de nova synthesis doesn’t happen there.
Hypoxanthine -> IMP via phosphoribosyltransferase
Guanine -> GMP via ^
Adenine -> AMP via. ^
Degradation of purine nucleotides,
AMP, IMP, GMP -> xanthine, degrades to Uric Acid via Xanthine oxidase.
Excessive uric acid condition
Treatment for this
Gout. Treatment with allopurinol. Allopurinol inhibits xanthine oxidase.
What does 6-Mercaptopurine (purinethol) do?
It is an anti-cancer drug.
Inhibits enzymes that convert IMP to AMP and GMP
These enzymes are IMP dehydrogenase, Adenylosuccinate synthetase
What does Hydroxyurea do?
Anti-cancer drug. Targets Ribonucleotide reductase.
Four more anti cancer drugs
Thioguanine
Cytarabine
5-Azacytidine
Gemcitabine
(Others were hydroxyurea and 6-mercaptopurine AKA purinethol)
Pyrimidine Synthesis
Glutamine (precursor) + Aspartate -> UMP
UMP can convert to C or T
Conversion of dUMP to dTMP
7,8 Dihydrofolate -> Tetrahydrofolate via Dihydrofolate reductase and NADPH.
Serine & NADPH contribute to methyl group.
Thymidylate synthase catalyzes dUMP -> dTMP
What do 5-Fluorouracil and Methotrexate inhibit?
5-Fluorouracil inhibits Thymidylate synthase
Methotrexate inhibits Dihydrofolate reductase
(Important for conversion of dUMP to dTMP)
Pdts of Pyrimidine nucleotide degradation
B-amino acids
CO2
NH3
