MOD 1.2 Midterm

deficient enzyme in cystinuria? presentation? lab result?

• cystine transporter (SLC3A1 + 7A9)

• cystine stones

deficient enzyme in phenylketonuria (PKU)? presentation? lab result?

• phenylalanine hydroxylase (PAH) *BH4

• musty odor, eczema, neuro disabilities, tremors

• low tyrosine/melanin, high phenylalanine/phenyl ketones

deficient enzyme in homocystinuria? presentation? lab result?

• cystathionine beta synthase (CBS) B6 OR met. synthase *B12

• ectopia lentis, skeletal w/ marfanoid features

• high homocysteine/methionine + low cysteine

deficient enzyme in alkaptonuria? presentation? lab result?

• homogentisate 1,2-dioxygenase (HGD)

• dark urine/skin/eyes, cartilage damage = stiff joints

• high homogentistic acid + low ketogenic substrate

deficient enzyme in maple syrup urine disease (MSUD)? presentation? lab result?

• branched-chain alpha-keto acid dehydrogenase (BCKDH)

• sweet smelling urine, muscular rigidity, seizures, opisthotonos, vomiting, lethargy

• ketosis + inc. BCAA (leucine, isoleucine, valine)

deficient enzyme in propionic acidemia? presentation? lab result?

• propionyl-coa carboxylase PCAA or PCCB gene

• vomit after feeding, seizures, coma, death, cardiomyopathy, hypotonia, encephalopathy

• VOMIT (dec. Val, OCFA, Met, Ile, Thr), AGMA, inc. propionic acid + ketones in urine

deficient enzyme in isovaleric acidemia? presentation? lab result?

• isovaleryl-coa dehydrogenase

• sweaty feet odor, vomit, encephalopathy, tachypnea

• ketoacidosis, hypoCa, hypoglycemia, hyperammonia

deficient enzyme in methylmalonic acidemia? presentation? lab result?

• methylmalonyl-coa mutase *B12

• renal failure, hypotonia, hepatomegaly, thrombopenia

• high MMCA, homocysteine, ammonia, ketoacidosis

what enzymes are deficient in proximal urea cycle disorders? labs? presentation?

• carbamoyl phosphate synthetase (CPS1) or N-acetyl glutamate synthase (NAGS) def.

  • low citrulline + Arg, hyperNH3, resp. alk., normal orotic acid

• ornithine transcarbamylase (OTC) def.

  • ““, high orotic acid + X-linked

• presentation → lethargy, vomit, seizure, cerebral edema

  • treat w/ protein restriction

what enzymes are deficient in distal urea cycle disorders? labs? presentation?

• argininosuccinate synthetase (ASS) (= same as prox.) OR argininosuccinate lyase (ASL) def.

  • high citrulline + glutamine, low arginine, hyperNH3, resp. alk

  • ASL → trichorrhexis nodosa (brittle, beaded hair)

• arginase-I def.

  • ““ + high arginine

  • spasticity, dev. delay, regression

primary carnitine deficiency lab results? presentation?

• OCTN2 or SLC22A5

• low plasma carnitine

• cardiomyopathy, muscle weakness, fasting intolerance

carnitine palmitoyl transferase I (CPT1) deficiency lab results? presentation?

• fxn: acyl-coa → acylcarnitine

• hypoketoic hypoglycemia, high free carnitine, low acyl carnitine

• hepatomegaly, poor feeding, lethargic, hypotonic

carnitine palmitoyl transferase II (CPT2) deficiency lab results? presentation? what other deficiencies cause this?

• fxn: acylcarnitine → acyl coa (B-ox)

• hyoketotic hypoglycemia, inc. C14-C18 acyl carnitines

• myopathy rhabdomyolysis, urine discoloration after exercise (myoglobin)

• also via: carnitine-acylcarnitine translocase (SLC25A20) (CACT)+ very long chain acyl coa dehydrogenase (VCLAD)

medium chain acyl coa dehydrogenase deficiency lab results? presentation?

• MCAD + ACADM/S/L

• hypoketotic hypoglycemia, inc. C6-C10 acyl-carnitines

• seizures, hepatomegaly, sudden death

full agonist? partial agonist? inverse agonist?

• full → produce same max response as endogenous ligand when binds receptor (=full efficacy)

• partial → produce partial response when binds receptor (regardless of conc.)

• inverse → produces opposite response to full or partial agonist when binds receptor

antagonist function? competitive vs non competitive?

• prevent agonist from binding receptor (but has no response when binds = affinity NOT efficacy)

• competitive (w/ agonist/reversible) → parallel + shifted up curve

• noncompetitive (diff. receptor/irreversible)

types of antagonism?

• pharmacological → same receptor

• physiological → agonist response mediated thru receptor is antagonized by agonist on different receptor

• chemical → forms complex w/ agonist to reverse its actions

therapeutic index? LD50? ED50? EC50?

• relates dose of a drug required to produce desired effect to that which produces undesired effect

• TI: LD50/ED50 → lethal dose for 50%/effective dose for 50%

• ED50 → which dose produces 50% max. response

• EC50 → effective conc. for 50% effect

down regulation? up regulation?

• down: phosphorylation → internalize membrane receptor + regulate receptor gene → # of receptors on membrane dec. (tolerance)

• up: chronic exposure to antagonist initially inc. response of receptor (super sensitivity), then inc. # of receptors on membrane surface

gradual (cont.) dose response curves? quantal (all or none) dose response curve?

• graded → btwn dose + magnitude of drug effect in particular tissue type

  • determine max. efficacy of drug in single subject

• quantal → btwn dose + cumulative percentage of subjects exhibiting an all or none effect

  • shows sensitivity of a pop. to a drug

additive effect? synergism? potentiation?

• additive → equal to sum of individual drug effect (e.g 2+2=4)

• synergism → effect is greater than sum of individual drug effects A & B (e.g 2+2>4)

• potentiation (similar to synergism) → drug B has no therapeutic effect alone, enhance therapeutic action of drug A (e.g 2+0>2) = parallel + left shifted curve

signal transduction pathway? permissive effect? tachyphylaxis?

• path → ligand bind = conformation change in receptor, receptor interaction w/ effector molecule/2nd messenger (cAMP, IP3, DAG, Ca) = response

• permissive → presence of substance A required for full effect of substance B

• tachyphylaxis → acute dec. response to drug after initial/repeated administration

affinity (KD)? efficacy or intrinsic activity? potency?

• affinity → ability to bind receptor

• efficacy → ability of drug to produce response

• potency → comparative measure of 2 drugs that produce same effect

what are GPCR? Ga subunit function? types?

• adrenoreceptors → act. via epinephrine

• Ga subunit = site of GTP hydrolysis

  • Ga (stim.) → B-adrenoreceptor + D1 dopaminergic

  • Ga (inhibit) → M2, a-adrenergic 2, D2 (MAD 2s)

  • Ga (stim.) → histamine 1, a-adrenergic 1, vasopressin, M1, M3 (HAVe 1 M&M)

Ga subunit mechanism?

• Gas (stim.) → inc. AC → inc. cAMP → act. PKA → phos. enzyme protein

• Gai (inhibit) → dec. AC → dec. cAMP → deact. PLA → dephos. enzyme protein

• Gaq (stim.) → act. phospholipase C → inc. IP3 + DAG → inc. Ca → combine w/ DAG → act. PKC → phos. enzyme proteins

ligand gated ion channel function? activation? receptors?

• open when they bind → ion channels open

  • act. via furosemide

• receptors:

  • GABAa: Cl ion flux → hyperpolarization

  • nicotinic receptor: Na ion influx → contraction

what are membrane bound enzymes? activation? receptors?

• cyclooxygenase, phospholipase A2

  • act. via aspirin + glucocorticoid

• receptors:

  • guanylate cyclase → atrial natriuretic factor (ANF)

  • tyrosine kinase → insulin, epidermal growth factor (EGF), nerve growth

nucleic acid role in protein receptors?

• act. by cyclophosphamide

• type 1 nuclear receptor: target for sex hormones

• type 2 nuclear receptor: for nonsteroid ligands like thyroid hormone, vit. A, vit. D, retinoid

what are the sphingolipidoses disorders?

• gaucher

• niemann pick A/B + C

• tay sachs

• krabbe

• fabry

• metachromatic leukodystrophy

deficient enzyme/gene in gaucher disease? characteristics?

• B-glucocerebrosidase (GBA)

• crumpled paper MO, hepatosplenomegaly, bone abnormality (aseptic necrosis, osteoporosis, pancytopenia)

deficient enzyme/gene in niemann pick A/B? characteristics?

• sphingomyelinase (SMPD1)

• foamy/lipid laden MO, cherry red spots, bone issues, hepatosplenomegaly

deficient enzyme/gene in niemann pick C? characteristics?

• NPC gene mut.

• above + speech problems, seizures, ataxia, down gaze palsy

deficient enzyme/gene in tay-sachs? characteristics?

• hexosaminidase A (HEXA)

• GM2 gangliosides accumulate, cherry red spots (retinal pallor) + neurodegeneration (seizures, weakness, blind → startle response)

deficient enzyme/gene in krabbde disease? characteristics?

• galactocerebrosidase

• globoid cells, demyelination (peripheral neuropathy + optic atrophy), fever, muscle weakness, stiff, posture, deafness seizures

deficient enzyme/gene in fabry disease? characteristics?

• a-galactosidase A (x-linked)

• skin issues, hypohidrosis, peripheral neuropathy, angiokeratomas

  • adult; cardio issues, stroke, renal failure

deficient enzyme/gene in metachromatic leukodystrophy? characteristics?

• arylsulfatase A (ARSA)

• central + peripheral demyelination → ataxia + dementia

  • neuro, hearing, vision + muscle/gait issues

what are the mucopolysaccharidoses disorders? what accumulates?

• hurler (MPS I) + hunter (MPS II)

• heparan + dermatan sulfate accumulate

deficient enzyme/gene in hurler (MPS I)? characteristics?

• a-L-iduronidase

• corneal clouding, glaucoma, coarse facial features, macrocephaly, bone/joint disease (dysostosis), hepatosplenomegaly, umbilical hernias, cardiac issues

deficient enzyme/gene in hunter (MPS II)? characteristics?

• iduronate 2 sulfatase (x-linked)

• aggression, bone disease, coarse features, cardiomegaly, death

deficient enzyme/gene in I cell disease? characteristics?

• mycolipidosis disorder

• N-acetylglucosamine (NAG) phosphotransferase GNPTA

• coarse features, umbilical hernias, MSK issues, cloudy corneas, gingival hyperplasia, macroglossia, inclusion cells accumulate

deficient enzyme/gene in pompe disease? characteristics?

• glycogen storage disorder

• lysosomal a-glucosidase (maltase)

• floppy baby, cardiomegaly, macroglossia, MSK weakness, dev. delays, pulm. issues