week 5 Flashcards
Defect in N-acetylglutamate synthase
unable to make N-acetylglutamate, lack activation of CPS-1, so urea cycle isn’t sped up; elevated ammonia in blood and urine, similar symptoms to CPS-1 deficiency
Defect in CPS-1
unable to make carbamoyl phosphate needed for urea cycle; elevated ammonia in blood and urine, no accumulation of urea cycle intermediates; low protein diet, arg supplementation, treatment to reduce ammonia levels (agents that remove glycine or glutamine from the system)
Defect in ornithine transcarbamoylase
most common urea cycle defect, X linked disease; hyperammonemia with orotic aciduria (high levels orotic acid)- precursor of pyrimidine synthesis, leads to buildup of carbomoyl-P in mito which diffuses into cytosol and stimulates pyrimidine synthesis
Defect in argininosuccinate synthetase
hyperammonemia, orotic aciduria to smaller extent, too much hypercitrullinemia (citrulline has no where else to go); hypercitrullinemia type I
Defect in argininosuccinate lyase
moderate hyperammonia with elevated levels of argininosuccinate
Defect in arginase
elevated arginine in blood, ammonia slightly elevated
treatments for urea cycle disorders
agents that conjugate with nitrogen containing compounds that will remove them from circulation; Benzoic acid- conjugates with glycine to form hippuric acid which is excreted; Phenylacetate- conjugates with glutamine to form phylacetylglutamine which is excreted; removing Gln means less chance of making ammonia
Hypercitrullinemia type II
citrin deficiency, protein that takes Asp out of mito in exchange for Glu in the cytoplasm; need Asp as a substrate, so citrulline can accumulate and so can ammonia; avoid carbs (otherwise NADPH will build up) and eat high protein, high fat diet
Cystinuria
defect in transport of Cystine, Lys, Arg, orthinine (dibasic amino acids), problems in kidney and intestines- poor absorption of these amino acids from gut and poor reabsorption from glomerular filtrate; Cystine (2 Cys connected via disulfide) accumulates in urine (cant be reabsorbed)- can precipitate and lead to kidney stones; drink lots of water for treatment; auto recessive
Hartnut disease
defect in transport of neutral amino acids (Ile, leu, phe, thr, trp, val), affects intestines and kidney; can be overcome by dipeptide transport systems; Trp deficiency is main problem because leads to trouble making NAD (if niacin is low); get pellagra symptoms; treatment is Trp and niacin supplementation, auto recessive
Cystinosis
lysosomal storage disease; can’t transport cystine out of lysosome; can lead to end stage kidney disease; treat with cysteamine which can break the cystines apart into products that can leave the lysosome
Rapamycin
drug that acts on mTOR, which is activated by AKT as part of the Ras pathway; mTOR is a surveillance center that assesses the cell nutrient status and simulates protein synthesis
ABL gene
non receptor tyrosine kinase, in leukemia (blood cancer), it becomes translocated and fuses to the BCR gene, which is constitutively active; Gleevac drug inhibits the action of the oncogene Abl-BCR product
Polycythemia vera
too many RBCs are made, another blood cancer; mutation usually in the JAK-STAT pathway (erythropoitin released from kidney binds JAK-STAT receptor) stimulating increased RBCs: Jakafi drug inhibits action of JAK
Protease inhibitors
inhibit degradation of proteins; useful for patients with multiple myeloma (Velcade-bortezimab); less degradation of excess antibody caused tumor cells to die from toxic buildup of proteins; also TF inhibitor doesn’t get broken down so growth factor genes aren’t transcribed- harmful for cancer cell growth
Leukocyte Adhesion Deficiency (LAD-1)
failure of leukocytes to migrate to infection site, due to CD18 deficiency (Type I), CD18 is beta subunit of LAF1 integrin, which is an adhesion molecule in blood vessels that directs leukocyte migration out of vessel (diapedesis) to the infection site; mutation leads to impaired wound healing because immune cells are not directed to the infection site
Chronic Granulamatous Disease
X linked condition where you have a mutation in phagocyte oxidase, which is necessary to kill bacteria through production of ROS; phagocytes still engulf microbes but are unable to kill, leading to granuloma formation because immune system tries to contain infection by surrounding with layer of cells
Drugs that inhibit microtubules
Colchicine- binds tubulin and prevents polymerization, used to treat gout; Toxol- binds microtubules and prevents depolymerization, chemo drug; Vinblastine- binds microtubules and prevents formation of mitotic spindle, chemo drug
Primary Ciliary Dyskinesia
loss of inner or outer dynein arms of cilia leads to impaired ciliary motility; leads to male and female infertility
Drugs that inhibit microfilaments
Cytochalosins: binds actin filaments and prevents polymerization; phalloidin: prevents depolymerization
Epidermolytic bullosa simplex (EBS)
deficiency of keratins (intermediate filaments) leads to blistering disease of the skin
Alcaptonuria
buildup of homogentisic acid, which oxidizes in air and turns black (black urine), may lead to arthritis
Phenylketonuria (PKU)
Classical: missing Phe hydroxylase; non-classical: missing tetrahydrobiopterin; leads to buildup of phenylpyruvate, phenyllactactate, phenylalanine; treatable with restricted Phe diet; if non-classical also need to supplement with THB, DOPA, 5-hydroxytryptophan
Tyrosinemia Type 1
lack of fumarlyacetoacetate hydrolase, leads to accumulation of succinylacetone and succinylacetate, leads to oxidative damage of liver and kidney; treat with low Phe and Tyr diet, nitisinone drug which blocks formation of homogentisic acid
