(L6) Protein and AA Metabolism Flashcards
How are AAs supplied to and depleted from the body supply of AAs?
L6 S7 LO1
Supply:
- degradation of protein
- dietary
- synthesis of AAs
Depletion:
- production of proteins
- synthesis of nitrogen compounds
- degradation of AAs
What is Hartnup disease?
L6 S7 LO1.a
Autosomal recessive defect in transporter for nonpolar/neutral AAs
Transporter found in the kidney and SI
How does Hartnup disease present?
L6 S7 LO1.a
Manifest as an infant
-failure to thrive
- nystagmus
- tremor
- ataxia (intermittent)
-photosensitivity
What is cystinuria?
L6 S7 LO1.a
Autosomal recessive defect in transporter for dimeric cystine and dibasic AAs
resluts in cystine cyrstals in kindeys which form renal calculi
How does cystinuria present?
L6 S7 LO1.a
Abdominal pain that comes in waves linked with formation of kidney stones, renal colic
What are exopeptidases and endopeptidases?
L6 S12 LO1.b
Exopeptidase:
-cleaves peptide bond from either the C or N terminus
Endopeptidase:
-cleaves peptide bond at specific site within protein
What are the major intracellular pathways of protein degradation?
L6 S13 LO1.c,d
Lysosomal/autophagy:
- non-selective
- occurs in the lysosome and requires acidic pH (~5)
Proteasomal:
- selective; requires protein to be ubiquinated
- occurs in cytoplasm by proteasome complex
What is the extracellular pathway of protein degradation?
L6 S14 LO1.d
Secreted, inactive zymogens which are activated by enterokinases
What are the different AA synthesis families?
L6 S11 LO1.f
- Pyruvate
- Glutamate
- Aspartate
- Serine
- Aromatic
What is the difference between ketogenic and glucogenic amino acids?
L6 S17 LO2.a
Ketogenic:
-can be converted into precursors for keto acids, ketones, or FAs (eg. acetyl CoA and acetoacetate)
Glucogenic:
-can be converted into precursors for gluconeogenesis (eg. pyruvate or TCA intermediates)
What are the ketogenic only amino acids?
L6 S17 LO2.a
- Leucine
- Lysine
What amino acids are both ketogenic and glucogenic?
L6 S17 LO2.a
- Isoleucine
- Phenylalanine
- Tryptophan
- Tyrosine
- Threonine
I Pee 3 Times
What is the reaction catalyzed by ALT?
L6 S21-22 LO2
Alanine aminotransferase
Pyruvate + Glutamate -> Alanine + α-ketoglutarate
Uses PLP (vitamin B6)
What is the reaction catalyzed by AST?
L6 S21-22 LO2
Aspartate aminotransferase
OAA + Glutamate -> Aspartate + α-ketoglutarate
Uses PLP (vitamin B6)
What is the reaction catalyzed by GA?
What is the significance of this?
L6 S21;23 LO2
Glutamine aminohydrolase
Glutamine + H20 -> Glutamate + NH3
Used to sequester free nitrogen in the brain.
What is hyperhomocysteinemia?
L6 S26 LO2
Results from deficiencies in cofactors (B6, B12, folic acid) or enzymes (cytationine β-synthase) that cause build up of homocysteine
Risk factor for ASHD, stroke, Alzheimer’s, lens dislocation, osteoporosis, and MR
What is maple syrup urine disease?
L6 S28 LO2
Autosomal recessive disease resulting from deficiency of branched-chain
α-keto acid dehydrogenase (BCKD) which is responsible for degrading branched chain AAs (isoleucine, leucine, and valine).
High concentrations of these AAs in the urine give it a smell simialr to maple syrup.
Treatment is limiting intake of these AAs.
What is the mechanism of phenylketonuria and how is it treated?
L6 S29 LO2
Defect in phenylalanine hydroxylase (PAH) which converts Phe into Tyr
Phenyllactate and phenylacetate are instead produced which block AA transport into brain and prevent myelin formation.
Treatment in limitation of Phe consumption with supplementation of Tyr
What are notable tryptophan derivatives?
L6 S34 LO3
Niacin
- requires B6
- used in NAD+/NADP+
5-hydroxytryptophan
- requires B6
- used in serotonin which is also used in melatonin
What are notable tyrosine derivatives?
What diseases are realized to tyrosine derivatives?
L6 S35 LO3
T3 and T4
-Graves’ disease and hyper/hypothyroidism
Melaninin:
-Albinism
Dopamine:
-Parkinson’s
Norepinephrine/epinephrine
What are notable arginine derivatives?
L6 S36 LO3
Creatine, creatine phosphate, and creatinine
How is ammonia removed from the brain?
L6 S40 LO4
α-ketoglutarate is aminiated to glutamate and glutamate is aminated to glutamine
Glutamine in shuttled to liver
How is ammonia removed from muscle?
L6 S41 LO4
Alanine is aminiated using ALT Alanine is shuttled to liver
What is the mechanism of ammonia toxicity?
L6 S45 LO4
Ammonia is able to cross cell membranes as it is uncharged (unlike ammonium)
This causes a pH imbalance, most notably in astrocytes in the brain resulting in:
- cerebral edema
- intracranial hypertension
TCA cycle is also disrupted due to depletion of α-ketoglutarate
What is the rate limiting step of the urea cycle?
Where does this occur?
L6 S43 LO4
Carbamoyl phosphate synthetase (in the mitochondria of the liver)
uses ammonium, bicarbonate, and ATP to form carbamoyl phosphate
Essential AA
pvt: phenylalanine, valine, threonine
Tim: tryptophan, isoleucine, methonine
hall: histadine, arganine, leucine and isoleucine
Phenylalanine makes
Tyrosine
ribose-5-phosphate makes
Histidine
Pyruvate makes
alanine
3 phosphoglycerate makes
serine –> cystine or glycine
Oxaloacetate makes
asparate –> asparganine
alpha-ketoglutarate makes
glutamate –> glutamine, proline or arginine
Exopeptidase vs endopetidase
attacks within the protein at a specific site
Intracellular proteolytic control
enzymes are controlled through marking mech that tags their protein substrates for degradation, this keeps intracellular enzymes from indicsimiatley degrading functional proteins
2 Types:
- Lysosomal/Autophagic System
- Protesomal degredation
Lysosomal/Autophagic System
have >50 hydrolase intracellular enzymes
-activate at pH of 5 in lysozme and inactive at pH of 7 (cytoplasmic)
- enzymes are nonslective
- 3 types: macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA)
Intracellular proteolytic control: CMA
Chaperone mediated autophagy: specifically recgonizes substrate
Intracellular proteolytic control: macroautophagy
uses multivesciular bodies (MVBs) to selectively deliver ubiqinated membrane proteins together with extracellular components to lysosomes
Intracellular proteolytic control: proteasomal degradation
proteasomal degradation: large proteasome cytoplasmic complexes that cleave polyubqinated proteins (selective pathway)
- catalytic core 20S with 7 subunits stacked on top of each other fo form a barrel
- OH of threonine acts as a nucleophile to attack carbonyl of peptide bonds
Extracellular proteolytic control
- proteolytic enzymes are secrated when needed
- secreted as zymogens and activated by proteolytic clevage
EX:
- inactive tryspinogen and chymo are releasead in SI lumen
- then ENTROKINASE is secreted and activates trypsin which activates chymo
glucogenic AA
the rest
-goes to become pyruvate or TCA cycle intermediates (turned into glucose via gluconeogensis)
Basic AA vs acidic aa
cysteine, orthine, arginine, cystine
asp, glu
AA metaoblism
1) Aminotransferases/ transaminase (ALT/AST) will transfer an amino group from the AA to a keto acid to make glutamate
2) glutamate dehydorgenase will act on glutamate via Nad–> NADH and produce NH4+
3) NH4 will enter the urea cycle
- the amine is shuffeled into the liver and repackaged as urea in the urea cycle
Transaminases need what?
-require coenzyme: pyridoxyl 5’ phosphate (a derivate of vitman B6)
How is alpha-ketoglutarate replenished?
Alpha-ketoglutarate is replenished by the anaplerotic reaction: glutamine -> glutamate -> alpha-ketoglutarate
-(glutaminase (a hydrolase) converts glutamine to glutamate and releases an NH4+)
Reverse Rxn:
-glutamine synthase takes on a NH4 to trap the nitrogen
-his, arginine and proline also can do this
What cofactor is shared with transaminases and cistionine beta synthase?
Pyridoxal phosphate (PLP)
Homocytinuria
Normally if all enzymes are working homocysteine is turned into MET
caused by 2 things:
-cystathionine beta-synthase mutation (needs Pyridoxal phosphate (PLP) as a coenzyme)
- HOMOCYSTEINE methyltransferase deficiency (needs vit b12)
- this causes hyperhomocysteinemia as it is built up as it can not get degraded
hyperhomocysteinemia and homocystinuria
Vitamin deficiencies (B6 (PLP), B12, folic acid) or genetic defects in enzymes (cystathionine β-synthase) cause defective metabolism of homocysteine
Hyperhomocysteinemia Sx
- risk factor for atherosclerotic heart disease
- stroke
- neuropscyh illnesses
BCAA Catabolism
Valine –> turned into succinyl CoA (Glucogenic)
Isoleucine –> can produce succinyl CoA and acetyl coa as it is both
leucine can produce acetoacetate and acetyl coa
ENZYME THAT ACTS ON IT IS ALPHA KETO ACID DEHYDROGENASE –> AND IT DOES OXIDATIVE DECARBOXYLATION
Deficiencies of these pathways can lead to maple syrup disease
Maple syrup urine disease (MSUD)
-rare autosomal diseases resulting from deficient branched-chain α-keto acid dehydrogenase complex (BCKD) activity which results in branched-chain ketoaciduria.
-Branched-chain amino acids present in the urine give the hallmark maple syrup smell.
Also accumulate in blood causing toxic effects on brain function and eventually mental retardation.
- treatement includes snythetic diet limiting BCAA
- Higher in Mennonite, Amish and Jewish populations
Metabolism of Phenylalanine
-Phenylalanine turns into tyrosine which turns into fumurate eventually
- this is done by phenylalanine hydroxylase
- deffiency in phenyalanine hydroxylase leads to –> (PKU)
Phenylketonuria
-PKU is caused by defects in the activity of phenylalanine hydroxylase (PAH)
Most common IEM; first IEM to be included in newborn screening
- Dietary limit Phe, protein supplied with synthetic formula supplemented with Tyr.
- Secondary PKU resulting from tetrahydrobiopterin deficiency (a cofactor of phenylalaninie hydroxlyase). Defects in synthesis or regeneration of BH4.
Most common IEM. What is a common symptom with it?
PKU. MUSTY ODOR IN URINE.
Tyrptophan AA derivative
can produce:
trp –> seritonin –> melatonin
trp —> nicanin —-(VIA vit b6)—-> nad+/NADP+
tyrosine AA derivates
- dopanine –> nor ep –> epi
- thryoid hormones (t3 and t4)
- melanin
Ketogenic AA
leucine and lysine
-goes to acetyl CoA or acetoacetate (eventually turned into ketone bodies and can not be turned into glucose)
Ketogenic and Glycolytic AA
Isoleucine, tryptophan, penylalanine, tyrosine, threonine (PITTT)
Creatine
- made from arginine, glycine, and methionine
- 1-2% is creatine phosphate (CP)
- excreted in the urine
- elevated serum levels of CP means kidney dysfunction and muscle degradation
- CP serves as energy storage in muscle, brain, and sperm
- it quickly generates ATP, and is used as our immediate energy source
- Cardiac isoform creatine kinase (CK-MB) diagnostic for MI
-can be turned into creatine, nonenzymatically
What is albimsim caused by?
- Albinism is due to severe lack of melanin
- Conversion of tyrosine to melanin is blocked due to defects in the enzyme tyrosinase
- Results in partial or complete absence of pigmentation in skin, hair and eyes
Thyroglobulin and thyroid hormones
- Thyroglobulin is a 660 kDa protein made by the thyroid and is used to produce T4 and T3
- T4 is the combination of 2 diiodinated Tyr
- T3 is the combination of 1 monoiodinated and 1 diiodinated Tyr; more potent than T4 but shorter half-life
If you cant make T3 and T4 –> Can cause Hypothyroidism –> which can lead to graves disease.
Hypothyroidism vs Hyper thyroidism
- High TSH, low T4
- Low TSH, high T4/3
Urea Sx
hepatic enceoplatophice, neurologica problems, toxic encphalophties
Removal of excess nh4 from brain
alpha keto gluterate -(glutamate dehydrogenase)-> glutamate -(glutamine synthase)-> Gln (carries the Nh3 out)
- Gln is than taken to the liver and turned into glu
- the free NH4 released by the glutimase then enters the urea cycle
What happens if there is to much ammonium
Glutamate dehydrogenase (GADH) keeps going on and on till it depletes the pool of alpha ketogluterate (CTA METABOLITE) and depletes ATP
Removal of excess nh4 from the muscles
- 1) pyruvate and glutamate react to form alanine and alphaketogluterate via (alanine aminotransferase with the coenzyme PLP)
(TRANS AMINATION RXN)
-2) ALANINE is then transfered to the blood then liver and then alanine and alpha ketogluterate come toghether and form pyrvate and glutamate
(TRANS AMINATION RXN)
-glutamate is then turned into alpha ketogluterate by glutamate dehydrogenase
(OXIDATIVE DEMAINATION RXN)
What is the RLS of the urea cycle and where does it happen?
MITOCHONDRIA OF THE LIVER (some times in kidney)
STIMULATED BY NAG……..
Removing nitrogen: ammonia
- Ammonia is removed as Glu and Gln in the brain via glutamine synthase
- it is removed as gln and ala in other tissues
Where is urea fromed
primarly liver but sometimes kidneys. It is excreted by the kindeys.
Urea cycle STEP ONE
- NH4 is turned into carbamoylphosphate via carbamoyl phosphate synthetase
- this step is rate limiting
- requires a bicarbonate and 2 ATP
What causes hyperammonemia?
Carbamoyl phosphate synthetase 1 deffiency
Ammonia tocitity slide****
Urea cycle and the high protein diet
urea production is increased by a high protein diet and decreased by high carb diet.
- Insulin and glucagon play a role in urea production
- About 20-30% of urea produced is hydrolyzed in the GI tract by bacterial urease
- Provides a source of ammonia nitrogen for gut bacteria, salvage and reuse
- High protein diets enhances this production and hydrolysis
