Biochem Flashcards
Causes of hyperammonemia
Most common = ornithine transcarbamylase deficiency (converts ornithine to citrulline in urea cycle): causes hyperammonemia and orotic aciduria.
Other causes: carbamoyl phosphate synthetase I deficiency (regulated by N-acetylglutamine). CPS I forms carbamoyl phosphate for the urea cycle
Causes of orotic aciduria
Ornithine transcarbamylase deficiency: hyperammonemia and orotic aciduria
UMPS deficiency (involved in de novo pyrimidine synthesis): hyperammonemia, megaloblastic anemia, mental retardation
RNA polymerases in euks
RNA pol I: makes rRNA, found only in nucleolus (Rampant - most common)
RNA pol II: makes mRNA (Massive - largest); opens DNA at promotor site. Inhibited by amanita mushrooms mRNA is read 5-3’
RNA pol III: makes 5S rRNA, tRNA (Tiny - smallest)
No proofreading function
RNA polymerase in proks
1 RNA polymerase (multisubunit complex) makes all 3 kinds of RNA. DNA-dependent RNA pol in proks is inhibited by Rifampin
Types of eukaryotic DNA pol
DNA pol alpha: replicates lAgging strand and makes RNA primer
DNA pol beta: repairs DNA
DNA pol gamma: replicates mtDNA (gamma = gaga = baby –> maternal…mtDNA)
DNA pol delta: replicates leaDing strand
DNA pol in proks
DNA pol I: excises RNA primer w/ 5-3’ exonuclease and replaces it with DNA
DNA pol III: elongates leading strand as well as lagging strand until it reaches primer of preceding fragment. 3-5’ exonuclease activity (proofread)
Hereditary fructose intolerance
AR deficiency in ALDOLASE B; causes accumulation of F1P and decrease in available phosphate –> reduced glycogenolysis/gluconeogenesis. Sx: hypoglc, jaundice, cirrhosis, vomiting. Decrease fructose & sucrose intake
Essential fructosuria
AR deficiency in FRUCTOKINASE; benign and asymptomatic. Hexokinase will take over and convert fructose to F6P. Sx: fructose in blood and urine
Galactosemia
AR deficiency in GALACTOSE-1-PHOSPHATE URIDYL TRANSFERASE (classic). galactose-1-P builds up. vom, feeding intolerance, jaundice, hepatomegaly soon after BF, and neonatal cataracts (galactose –> galactitol).
Milder form = GALACTOKINASE deficiency; neonatal cataracts which may p/w inability to track objects or lack of social smile, but otherwise asymptomatic. galactose builds up in blood, urine
PKU
Inability to convert Phe to Tyr d/t deficient Phe hydroxylase. Tyr becomes essential AA. Features: mental retardation, seizures, light pigmentation, musty body odor
Cystinuria
Defect of renal PCT & intestinal AA transporter prevents reabsorption of COLA (cystine, ornithine, lysine, arginine). Excess cystine in urine –> hexagonal cystine stones. Dx w/ cyanide-nitroprusside test; Tx: alkalinize urine (acetazolamide, potass citrate), chelate, hydrate
Homocystinuria
3 types:
- cystathionine synthase (CS) deficiency: can’t form cysteine from homocysteine. tx w/ decreased methionine, increased cysteine, B6, B12, folate.
- reduced affinity of CS for pyridoxal phosphate. Tx w/ lots of B6 and cysteine
- Methionine synthase deficiency: can’t form methionine from homocysteine. tx w/ increased methionine
HOMOCYstinuria: high urine Homocysteine, Osteoporosis, Marfan habitus, Ocular changes (down/in sublux), CV effects (thrombosis/atherosclerosis), kYphosis + intellectual disability
Number of Cal/gram of various metabolic fuels (1 Cal = 1 kcal)
(# letters = # Cal)
1g CARB/protein (e.g. WHEY) = 4 Cal
1g ALCOHOL = 7 Cal
1g FATTY ACID = 9 Cal
Wernicke-Korsakoff syndrome
B1 (thiamine) deficiency causing confusion, ophthalmoplegia, ataxia [wernicke] + later IRREVERISBLE mem loss, confabulation, personality change [korsakoff]. Damage to medial dorsal nucleus of thalamus and mammillary bodies. Dx w/ low RBC transketolase (will increase after giving vit B1).
Giving dextrose alone to a thiamine-deficient pt (e.g. an alcoholic) can precipitate Wernicke encephalopathy d/t increased thiamine demand
Gluconeogenesis irreversible enzymes
- Pyruvate carboxylase (pyruvate –> oxaloacetate). Requires biotin, activated by acetylCoA
- PEP carboxykinase (oxaloacetate –> PEP). Requires GTP
- F-1,6-bisphosphatase (F16BP –> F6P). Activated by ATP, glucagon; inhibited by AMP, F26BP
- Glucose-6-phosphatase (G6P –> glc)
Rate limiting enzymes for:
- de novo pyrimidine synthesis
- de novo purine synthesis
- glycolysis
- gluconeogenesis
- glycogenesis
- glycogenolysis
- TCA
- HMP shunt (PPP)
- urea cycle
- pyrimidine: CPS2 (in cytosol, gets N from glutamine)
- purine: glutamine PRPP amidotransferase
- glycolysis: PFK1
- gluconeogenesis: F-1,6-bisphosphatase
- glycogenesis: glycogen synthase
- glycogenolysis: glycogen phosphorylase
- TCA: isocitrate dehydrogenase
- HMP: G6PD
- urea cycle: CPS1 (in mitoch, gets N from ammonium)
Cofactors for pyruvate dehydrogenase and a-KG dehydrogenase complexes
Help convert pyruvate to AcetylCoA for TCA, and isocitrate to a-KG in TCA. "The Lovely Co-enzymes For Nerds": Thiamine pyrophosphate (B1) Lipoic acid CoA (B5, pantothenic acid) FAD (B2, riboflavin) NAD (B3, niacin)
4 fates of pyruvate
- AcetylCoA (TCA)
- Lactate (Cori cycle)
- Oxaloacetate (gluconeogenesis or replenish for TCA)
- Alanine (Cahill cycle)
Mnemonic for each step in TCA
“Citrate Is Krebs’ Starting Substrate For Making Oxaloacetate”: citrate, isocitrate, a-KG, Succinyl-CoA, Succinate, Fumarate, Malate, Oxaloacetate
Steps of TCA inhibited by alcoholism/thiamine deficiency
Steps requiring NAD+ will be inhibited, as aldehyde dehydrogenase consumes NAD+ and increases the NADH/NAD+ ratio. These steps are malate –> oxaloacetate by malate dehydrogenase, isocitrate to a-KG by isocitrate dehydrogenase, and a-KG to succinyl-CoA by a-KG dehydrogenase.
a-KG –> succinyl-CoA will be particularly affected bc it also requires thiamine (B1) as a cofactor. Conversion of pyruvate to Acetyl-CoA by pyruvate dehydrogenase (to enter TCA) is also thiamine-dependent
4 consequences of increased NADH/NAD+ ratio caused by alcohol metabolism
- pyruvate gets shunted to lactate, causing lactic acidosis
- oxaloacetate –> malate (backwards TCA): prevents gluconeogenesis, causing fasting hypoglc
- DHAP –> G3P (combines w/ FA’s to make TAGs) –> hepatosteatosis
- TCA slowed down to prevent making more NADH, so acetyl-CoA gets shunted to ketogenesis and lipogenesis, causing ketoacidosis and hepatosteatosis
Hartnup disease
Deficiency of neutral AA (e.g. Tryptophan) transporters in PCT & enterocytes –> neutral aminoaciduria and pellagra-like sx (don’t have Tryp and can’t convert it to Niacin). Tx: high protein diet, nicotinic acid
Pellagra sx: diarrhea, dermatitis, dementia
Alkaptonuria
Deficiency in homogentisinate oxidase, which is required to degrade Tyr to Fumarate to enter TCA. Homogentisic acid builds up –> pigment (bluish-black connective tissue, ear cartilage, sclerae); turns urine black on prolonged exposure to air; severe arthralgias (toxic to cartilage)
AA precursors of:
- porphyrin and heme
- NO
- GABA
- histamine
- SAM
- creatine
- porphyrin and heme: glycine
- NO: arginine
- GABA: glutamate
- histamine: histidine
- SAM: methionine
- creatine: arginine
FPBase2/PFK2 bifunctional enzyme complex, and activity in fed vs. fasting state
- Fed state: increased insulin stimulates glycolysis, increasing the activity of PFK2 to convert F6P to F2,6BP. Increased F2,6BP stimulates PFK1 to continue glycolysis/inhibits gluconeogenesis
- Fasting state: high glucagon stimulates gluconeogenesis, increasing the activity of FBPase2 to convert F2,6BP to F6P to make glucose/inhibits glycolysis
Medium-chain acyl-CoA dehydrogenase deficiency
Reduced ability to break down FA’s into acetyl-CoA, resulting in hypoketotic hypoglycemia after prolonged fasting. Will also have low carnitine; lethargy, vom, seizures, coma, liver dysfxn, hyperammonemia, sudden death in infants/kids. Tx by avoiding fasting
Systemic primary carnitine deficiency
Inherited defect in transport of LCFAs into mitoch –> toxic accumulation. Causes weakness, hypotonia, hypoketotic hypoglc
Cyanide toxicity causes, presentation and treatment
Cyanide binds cytochrome c oxidase in ETC, preventing ATP prodxn. Toxicity can occur in pts treated w/ nitroprusside for HTN crisis (releases cyanide), or inhaling burning fumes of polyurethane or vinyl. P/w AMS, seizure, CV collapse, lactic acidosis, bright red venous blood. Tx: hydroxycobalamin (directly binds cyanide ions), induce methemoglobinemia (binds up cyanide) with a nitrite, and detoxifying sulfur donors (thiosulfate)
