Part 6.1 Flashcards
About acetaminophen
Indications
Toxicity concerns
Treatments
AKA paracetamol or Tylenol
NSAID class
Indications: analgesic and antipyretic (minimal anti-inflammatory effect)
Toxicity concerns: NAPQI oxidation metabolite causes hepatocellular damage and liver failure
Treatments: N-acetylcysteine as GSH precursor can metabolize NAPQI or activated charcoal
- Can cause GI bleeding - don’t take on empty stomach
Pathways to metabolize paracetamol
Oxidation to NAPQI, conjugation by GSH
Deacetylation (1-2%) to p-aminophenol
Glucuronidation conjugation to paracetamol glucuronide
Sulfation to paracetamol sulfate
Conversion of Phe to Tyr
Phe + O2 –> Tyr + H2O by phenylalanine hydroxylase
What is PKU?
Treatment for PKU
PKU = phenylketonuria
Autosomal recessive genetic disorder where no phenylalanine hydroxylase is produced to convert Phe –> Tyr
Excess Phe produced phenylketones excreted in urine
- toxic to the developing brain
Treatment:
- Tyr becomes indispensable AA
- medical nutritional therapy (keep Phe content low)
- must be diagnosed right after birth (fetus is protected)
Sickle Cell Anemia about
Sickle cell is a single nucleotide polymorphism where glutamate in hemoglobin is replaced with a valine residue
Causes blood cell to sickle, and get sticky and clump easily
- Doesn’t carry oxygen well
Proposed sickle cell anemia therapy
CRISPR-cas9 gene editing to produce fetal hemoglobin which has 2 alpha/2 gamma subunits instead of 2 alpha/2 beta (adult)
- great oxygen affinity
BCL11A - shuts off fetal hemoglobin production soon after birth
CRISPR-cas9 therapy would disable BCL11A so that fetal hemoglobin production would continue
- extracts blood producing stem cells to destroy BCL11A
- destroy stem cells and then reintroduced edited stem cells
Cystic fibrosis about
Symptoms
Treatments (5)
Autosomal recessive genetic disorder which leads to poorly functioning/misfolded chloride channel CFTR (conductance regulator protein)
- 2000 known polymorphisms which cause it
Symptoms:
1) produces thick mucous in lungs - vulnerability to infections
2) No production of pancreatic enzymes - Prone to fat-soluble vitamin deficiency
Treatment:
1) physiotherapy to break mucus up
2) treated with enteric coated enzymes) - improves digestion
3) lung transplants
4) Trikafta - 3 medications to: stabilize CFTR and increase migration to membranes
- only 10% functionality required from chloride channels
5) CRISPR-cas9 in the future?
Conditionally indispensable arginine de novo pathway
When is it indispensable?
Effect of arginine deficiency
Treatment
1) Glutamate or proline consumed –> citrulline (intestine)
2) Citrulline –> arginine (kidney)
Indispensable: sick babies can’t make enough, illness, feeding regimens, disfunction in conversion
Arg deficiency: low protein synthesis isn’t affected but ammonia detoxification is (high protein turnover urea cycle disrupted)
- produces tremors, seizures and potentially death
Treatment: Therapy with either arginine or citrulline corrects deficiency
Alanine Cahill cycle
Muscle:
Glucose –> pyruvate + (2 ATP produced) –> alanine
Liver:
Alanine –> –> pyruvate –> glucose (costs 6 ATP)
Alanine acts as transport of NH4+ from muscle for urinary excretion
ALT - alanine aminotransferase
Serine synthesis
Serine can be produced from 3-phosphoglycerate from glycolysis/gluconeogenesis
AA made from TCA intermediates (3)
Oxaloacetate –> aspartate + NH3 –> asparagine
a-ketoglutarate –> glutamate + NH3 –> glutamine
glutamate –> glutamate semialdehyde –> proline
Synthesis of alanine from pyruvate
Pyruvate + glutamate –> alanine
Arginine synthesis from ornithine (starting at glutamate semialdehyde)
Glutamate semialdehyde + Glu –> ornithine
Ornithine (via urea cycle) –> arginine
Serine synthesis 2 ways
Cysteine synthesis from serine
Glucose or glycerol (TA) + Glu or alanine (TA) –> serine
OR 3-phosphoglycerate –> serine
Serine + homocysteine (from Met) –> cystathionine
Cystathionine –> cysteine
Creatine kinase in muscle
Converts creatine + ATP –> phosphocreatine + ADP
Converts phosphocreatine + ADP –> creatine + ATP
