5/3 Biochemistry Flashcards
Pyruvate Kinase Deficiency
Red Pulp Hyperplasia
Pyruvate kinase deficiency causes hemolytic anemia due to failure of glycolysis and resultant failure to generate sufficient ATP to maintain erythrocyte structure. Splenic hypertrophy results from increased work of the splenic parenchyma (hyperplasia of reticuloendothelial cells), which must remove these deformed erythrocytes from the circulation.
Lactic acidosis in septic shock
Due to tissue hypoxia > impairs oxidative phosphorylation
Causes shunting of pyruvate to lactate following glycolysis. Hepatic hypoperfusion also contributes to the buildup of lactic acid as the liver is the primary site of lactate clearance.
Risk factor and presentation for aspiration pneumonia
Risk factor: dementia and hemiparesis (vocal cord paralysis= soft, breathy voice)
Presentation: rhonchi, dense air space opacities in superior region of lower lobes or posterior region of upper lobes (dependent locations) on CXR
Cause of Ehlers-Danlos that is a result of a defect in the extracellular processing of collagen
N-terminal propeptide removal
Due to procollagen peptidase deficiency
Alkaptonuria
AR disorder of tyrosine metabolism (prevents conversion of tyrosine to fumarate)
Lack of homogentisic acid dioxygenase leads to accumulation of homogentisic acid
BLACK URINE when exposed to air, blue-black pigment on face (sclera, ear cartialge), ochronotic arthropathy, severe arthritis in adults
Mutation causing gout
X-linked mutation affecting the phosphoribosyl pyrophosphate (PRPP) synthetase gene - activating mutation causing increased production and degradation of purines
Cell type responsible for the intense inflammatory response seen in gout
Neutrophils
Rx with NSAIDs (or colchicine if NSAIDs are contraindication)
Acute gouty arthritis
Primary carnitine deficiency
Myopathy (high creatine kinase, weakness), cardiomyopahy (S3 gallop), hypoketotic hypoglycemia w/ decreased muscle carnitine content
Impaired fatty acid transport from cytoplasm into mitochondria, prevents B-oxidation of fatty acids in acetyl CoA
Cardiac and skeletal muscle injury, impaired ketone production during fasting
Deficient synthesis of acetoacetate
Fructokinase deficiency
‘Essential fructosuria’
Asymptomatic, AR, fructose is excreted unchanged in urine
Hexokinase takes over role of fructose metabolism (converts to fructose 6 phosphate which will enter glycolysis)
Niemann Pick disease
AR, sphingomyelinase deficiency
Sphingomyelin accumulation within lysosomes, lipid laden foam cells, hepatosplenomegaly
Hypotonia, neurologic degeneration, cherry red macular spot
NOTE: NO HEPATOSPLENOMEGALY seen in Tay-Sachs, otherwise very similar
Restrict this substance in diet to improve condition in patient with impaired transport of ornithine from cytosol to mitochondira
Protein
Urea cycle defect
Vitamin C deficiency (scurvy)
Vit C is necessary for hydroxylation of proline and lysine residues in pro-collagen
Most often seen in severely malnourished individuals
Capillary bleeding, poor wound healing, periodontal disease (bony deformities and subperiosteal hemorrhages in children)
G protein coupled receptors
Bind glycoprotein hormones (TSH, LH, FSH)
Transmembrane domain is composed of alpha helices with hydrophobic amino acids (alanine, valine, leucine, isoleucine, phenylalanine, tryptophan, methionine, proline, glycine)
Transmembrane domain anchors the protein to the phospholipid bilayer of cell membrane
Folate Deficiency: administration of which supplement would reduce erythroid precursor cell apoptosis?
Folate deficiency inhibits formation of dTMP, limiting DNA synthesis and promoting megaloblastosis and erythroid precursor cell apoptosis
Thymidine supplementation can moderately increase dTMP levels and reduce erythroid precursor cell apoptosis
Biotin (vit B7) as a cofactor for enzymes, Biotin deficiency
- can be due to consumption of raw egg whites
- mental changes, myalgias, anorexia, macular dermatitis, lactic acidosis
- Pyruvate carboxylase (pyruvate to oxaloacetate w/ gluconeogenesis)
- acetyl-CoA carboxylase (acetyl-coA to malonyl-CoA in fatty acid synthesis)
- Propionyl-CoA carboxylase (propionyl-CoA to methylmalonyl-CoA in fatty acid oxidation)
Binding of oxygen to hemoglobin drives the release of….
H+ and CO2 from hemoglobin (Haldane effect)- lungs
vs. in peripheral tissues, high concentrations of CO2 and H+ facilitate oxygen unloading from hemoglobin (Bohr effect)
Which enzyme has 5’ to 3’ exonuclease activity in addition to 3’ to 5’ exonuclease activity and 5’ to 3’ polymerase activity
DNA pol I in prokaryotes
5’ to 3’ exonuclease activity removes RNA primer and repairs damaged DNA sequences
Homocystinuria
- defect in cystathionine synthase
- inability to form cysteine from homocysteine
- Cysteine is essential in the diet
- Homocysteine builds up and is prothrombotic, resulting in premature thrombolic events (atherosclerosis, acute coronary syndrome)
Hemoglobin C
Missense mutation (glutamate for lysine) in beta globin cahin
Overall decrease in negative change for hemoglobin molecule
Speed of hemoglobin movement:
Hemo A > hemo S > hemo C
Congenital deficiency of propionyl CoA carboxylase
Enzyme responsible for conversion of propionyl CoA to methylmalonyl CoA
Leads to development of propionic acidemia
Propionyl CoA is derived from amino acids (Val, Ile, Met, Thr), odd-numbered fatty acids, cholesterol side chains
Poor feeding, vomiting, hypotonia, lethargy, dehydration, anion gap acidosis
PKU
Tyrosine is ESSENTIAL, restrict phenlalanine
Deficiency in phenylalanine hydroxylase (phenlalanine to tyrosine)
Fair complexion (lack of melanin), seizures, eczema, MUSTY ODOR
Amatoxins (poisonous mushrooms, death cap)
Potent inhibitors of RNA polymerase II (halts mRNA synthesis)
Symptoms start 6-24 hours after ingestion: abd pain, vomiting, severe cholera-like diarrhea (with blood and mucus, acute hepatic and renal failure
urine testing for a-amanitin can confirm suspected poisoning
How does insulin promote glycogen synthesis
Acts via receptor tyrokine kinase, stimulates phosphatidylinositol-3-kinase which activates protein phosphatase, which dephosphorylates/activates glycogen synthase
Increases synthesis of glycogen, proteins, fatty acids, nucleic acids
Process of forming cataracts due to long term hyperglycemia
Glucose is converted to sorbitol by aldose reductase
Sorbitol is converted to Fructose by Sorbitol dehydrogenase
The lens contains high levels of sorbitol dehydrogenase, but this becomes overwhelmed with hyperglycemia
Sorbitol is trapped in the cells, increases osmotic pressure, facilitates influx of water into lens cells, hydropic lens fibers that degenerate , len opacification and cataract formation
Mitochondrial DNA (mtDNA)
Most common non-nuclear DNA found in eukaryotic cells
Resembles prokaryotic DNA (small circular DNA molecules)
Maternally derived
Mutations involving mtDNA can cause mitochondrial disorders (ex. Leigh syndrome, MELAS)
Thiamine (Vit B1) Deficiency
Beriberi
Dry: symmetrical peripheral neuropathy of distal ext. with sensory and motor impairments
Wet: + cardiac involvement (cardiomyopathy, high-output CHF, peripheral edema, tachycardia)
If neuro symptoms (esp w/ alcoholic, think Wernicke-Korsakoff)
Primary myelofibrosis
Chronic myeloproliferative disorder
Caused by atypical megakaryotic hyperplasia, stimulates fibroplast proliferation, replacement of marrow space with collagen
Severe fatigue, splenomegaly, , early satiety/abdominal discomfort, hepatomegaly, anemia, bone marrow fibrosis
Mutation in JAK2, a cytoplasmic TK, leads to cytokine independent activation of signal transducers and activators of transcription (STAT proteins)
Riboflavin deficiency
Ribofalvin is precursor to coenzymes FMN and FAD
FAD participates in TCA cycle and electron transport chain as electron acceptor for succinate dehydrogenase (succinate into fumarate)
Low riboflavin excretion, seen in chronic alcoholics and severely malnourished
Angular stomatitis, cheilitis, glossitis, seborrheic dermatitis, eye changes, anemia
Maple Syrup Urine Disease
Defect in a-keto acid dehydrogenase
Inability to degrade branched chain amino acids
Dystonia, poor feeding, “maple syrup scent” of patient’s urine w/n first few days of life
Rx: restrict intake of branched chain amino acids (leucine, isoleucine, valine)
PI3K/Akt/mTOR pathway
Intracellular signaling pathway important for anti-apoptosis, cellular proliferation, angiogenesis
Mutations in growth factor receptors, Akt, mTOR or PTEN that enhance the activity of this pathway contribute to cancer pathogenesis
Causes translocation of mTOR to nucleus and gene transcription
Maturity-onset diabetes of the young
Mild, nonprogressive hyperglycemia that often worsenes with pregnancy-indced insulin resistance
Heterozygous mutation of glucokinase gene > decrease in beta cell metabolism of glucose, less ATP formation, and less insulin release
Glucokinase functions as a glucose sensory
Biochemical process defective n Parkinson’s
Ubiquitination
Impairment of the ubiquitin-proteasome system can contribute to the development of neurodegenerative disorders, including Parkinson’s and Alzheimer’s disease
Signal transduction of phospholipase C
Ligand-receptor binding and Gq protein activation, activation of phopholipase C (PLC), PLC hydrolyzes PIP2 and forms DAG and IP3. IP3 activates protein kinase C via an increase in intracellular Ca
What is the effect of insulin on gluconeogenesis/glycolysis?
Fructose 2,6-bisphosphate activates phosphofructokinase 1 (increasing glycolysis) and inhibits fructose 1,6-bisphosphatase (decreasing gluconeogenesis)
Fructose 2,6 bisphosphate concentration is decreased in the presence of insulin and decreases in response to glucagon
What inhibits beta-oxidation of fatty acids?
Malonyl-CoA
Cytosolic acetyl-CoA carboxylase converts acetyl-CoA to malonyl-CoA during the rate limiting step of de novo fatty acid synthesis. Malonyl CoA inhibits the action of mitochondrial carnitine acyltransferase, thereby inhibiting beta-oxidation of newly formed fatty acids
Synchronization of glycogen degradation with skeletal muscle contraction occurs due to…
Release of sarcoplasmic calcium following neuromuscular stimulation. Increased intracellular calcium causes activation of phosphorylase kinase, stimulating glycogen phosphorylase to increase glycogenolysis
Arginase deficiency
Progressive development of spastic diplegia, abnormal movements, growth delay, elevated arginine levels
Arginase is a urea cycle enzyme that produces urea and ornithine
Rx: low protein diet devoid of arginine, admin of synthetic protein
Note: Patients have mild or no hyperammonemia (vs. other urea cycle disorders..)
Lactate dehydrogenase deficiency
In anaerobic glycolysis, NAD+ is regenerated from NAHD when pyruvate is converted to lactate via lactate dehyrdrogenase.
In patients with lactate dehydrogenase deficiency, glycolysis is inhibited in strenuously exercising muscle as muscle cells cannot regenerate NAD+. Consequently, high intensity physical activity leads to muscle breakdown, pain, and fatigue as insufficient amounts of energy are being produced in th exercising muscle.
Hemoglobin F
2 Alpha chains and 2 gamma chains (present for the first few weeks of post natal life)
Patients with homoxygotic B-thalassemia are asymptomatic at birth due to presence of gamma globins and HbF
Renal acid excretion in chronic acidotic states
Acidosis stimulates renal ammoniagenesis: renal tubular epithelial cells metabolize glutamine to glutamate, generating ammonium that is excreted in the urine and bicarbonate that is absorbed into the blood.
Acute ischemic colitis (due to embolic disease from a fib). Ischemic bowel undergoes anaerobic metabolism, causing lactate accumulation in the blood, leads to an anion gap metabolic acidosis.
Pigmented gallstones
Composed of calcium salts of unconjugated bilirubin and typically arise secondary to bacterial or helminthic infection of the biliary tract.
Beta-glucuronidase released by injured hepatocytes and bacteria hydrolyzes bilirubin glucuronides to unconjugated bilirubin.
The liver fluke Clonorchis sinensis has a high prevalence in East Asian countries and is a common cause of pigment stones.
Cyanide poisoning
Toxicity of cyanide is dependent on its ability to binds ferric iron (Fe3) with high affinity, inhibiting cytochrome c oxidase in mitochondria (essential for oxidative phosphorylation). Inhibition results in severe lactic acidosis and death.
Redding skin, tachypnea, headache, tachycardia, N/V, confusion, weakness. Seizures, cardiovascular collapse.
Administration of inhaled amyl nitrite oxidizes ferrous iron (Fe2) present in hemoglobin to ferric iron (Fe3), generating methemoglobin. Methemoglobin is incapable of carrying O2 but has a high affinity for cyanide. It binds and sequesters cyanide in the blood, freeing it from cytochrome oxidase.
Production of ribose from fructose-6-phosphate
Transketolase and transaldolase carry out the nonoxidative reactions of HMP shunt. Some cells do not use the oxidative phase reactions to produce cytosolic NADPH, but all cells can synthesize ribose from fructose-6 phosphate using the non-oxidative reactions.
Lead toxicity
Young children, impoverished, who reside in homes built bedore 1978 are at significant risk for lead toxicity.
Lead directly inhibits ferrochelatase and delta-aminolevulinic acid (ALA) dehydratase, resulting in anemia, ALA accumulation, and elevated zinc protoporphyrin levels. Neurotoxicity is also a significant longterm complication.
Fabry’s disease
galactosidase A deficiency
Neuropathic pain, angiokeratomas, decreased sweating, renal failure, cardiac/stroke
Acute intermittent porphyria attacks
Due to accumulation of aminolevulinate (ALA) and porphobilinogen (PBG), resulting from inherited PBG deaminase deficiency combined with ALA synthase induction (typically due to certain medications, alcohol use, or a low calorie diet).
Management with glucose or hemin inhibits ALA synthase activity.
Oxygen-hemoglobin dissociation curve
Left curve: Decreased H+ Decreased 2,3 DPG Decreased temperature Think LUNGS= Left shift O2 is less available to tissues
Right curve:
Increased H+
Increased 2,3 DPG
Increased temperature
Under normal circumstances, KRAS is only active when bound to….?
GTP
The regulation of the Ras-MAPK signal transduction pathway requires a balance between active (GTP-bound) and inactive (GDP-bound) Ras proteins.
RAS gene mutations, which result in constitutively activated Ras proteins, are implicated in the development of malignant tumors.
Phenylketonuria (PKA)
Severe intellectual disability, history of seizures, abnormal pallor of catecholaminergic brain nuclei on autopsy, MUSTY/mousy odor
Inability to convert phenylalanine into tyrosine (phenylalanine hydroxylase or cofactor tetrahydrobiopterin deficiency)
Tay-Sachs
AR, B-hexosaminidase A deficiency, accumulation of GM2 ganglioside
Progressive neurologic deterioration, weakness, hypotonia, developmental regression, seizures, blindness, spasticity, macrocephaly, abnormal startle reflex, cherry-red macula spot (with white macula halo)
NO HEPATOSPLENOMEGALY (vs. Niemann Pick)
Heme oxygenase
Found in macrophages
Degrades heme into biliverdin (green) > which is further reduced into bilirubin (yellow) by biliverdin reductase
Causes bruises to turn green
Diabetic ketoacidosis: what is the cause of increased glucose?
Increased triglyceride breakdown in adipose tissue due to insulin deficiency.
Glycerol is converted to glycerol-3-phosphate in the liver by glycerol kinase. Then DHAP is formed, which can produce ATP (through glycolysis) or glucose (through gluconeogenesis)
Glycerol produced by degradation of triglycerides in adipose tissue can be used by glycerol kinase in the liver and kidney to synthesize glucose during gluconeogenesis.
