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128 Cards in this Set
- Front
- Back
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Parkinson's DZ
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substantial degeneration of the dopaminergic cells in the substantia nigra occurs in parkinsons
1st major dopamine pathway |
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mesocorticolimbic pathway
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2nd pathway of dopamine creation
implicated in action of drugs of addiction |
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Is NE a vasoconstrictor or vasodilator
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vasoconstrictor
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origin of NE in brain
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locus coeruleus
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NE function in brain
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vigilance
attention memory consolidation learning rage aggressiveness sleep-wakeful cycles and neuroendocrine functions |
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function of epinephrine
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synthesized in adrenal medulla
-key to fights or flight response -increases glucose and lipid utilization by heart an muscle to deal with emergencies or threats to homeostasis |
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catecholamine synthetic pathway
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107FA
lecture notes 417 |
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fate determining step in catecholamine synthesis.....also talk about it
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-Tyrosine Hydroxylase
-has short and long term regulation short term.... -depolarization ^ -cAMP ^ -tetrahydrobiopterin ^ *there are several serine residues of the tyrosine hydroxylase enzyme that when hydroxylated cause increased activity (can be hydroxylated by many different kinases) -Serine40 is very important Long Term -occurs when there is enhanced activity for a long time -several physiological and pharmacolgical stimuli can now increase transcription of enzyme to make more of it: stress, nicotine, etc. -cAMP, calcium regulatory element and AP1 are very important |
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Dopamine Beta hydroxylase locations
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-present in neurosecretory vesicles
-dopamine is synthesized in cytosol and transferred to the vesicles -aso found in membrane, and soluble content of neurosecretory vesicles and chromaffin granules in adrenal medulla |
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Dopamine Beta Hydroxylase regulation
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long term regulation
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Phenylethanolamine N methyl transferase regulation
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long term by cludocorticoids
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which enzyme in catecholamine pathway is not found in cytosol
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dopamine B hydroxylase
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What do neuronal re-uptake transporters do and talk about clinical importance with drugs
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-they allow the catecholamine to be taken away from the synapse so its effect can be subdued
-dopamine uptake 1 transporter is inhibited by cocaine -tricyclic antidepresents inhibit NE transporter |
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2 main enzymes used in inactivation of catecholamines
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1)Monoamine oxidase: present in mitochondria membranes.....deaminates surplus catecholamines with leak out vesicles
Catechol-O-Methyltransferase: present in non neuronal cells. Methylates a hydroxyl group of the catechol, using SAM as methyl donor. alterations in enzymes have disorders of NS |
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Catecholamine degredation pway
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ln 420
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main metabolic products of catecholamine in effector cells and sympathetic nerve terminals
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effector
1)NE and epi: MHPG and VMA 2)HVa sympathetic 1) NE and epi: DHPG 2) DOPAC |
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talk about following disease....characteristics and clinical features
parkinson's DZ essential hypertension DBH deficiency depression stress Pheochromocytoma Drug Abuse |
L 422
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how much heme is made each day in the bone marrow
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6-7 grams
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name 6 functions of heme
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hemoglobin: o2 transport in blood
myoglobin: o2 storage in muscle cytochrome c: eTC cytochrome P450: steroid and drug met catalase: degradation of h202 signal transduction |
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3 types of porphyrins with side structure
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L 426
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Hemin
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heme containing iron 3+ with counterion usually chloride
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hematin
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heme containing iron 3+ with counterion usually hydroxide
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heme synthetic pathway and mnemonic
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FA 348
L427 S-GAP-HUC-PPH |
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rate limiting step in heme synthesis
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ALA synthase found in mitochondria
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which step in heme synthesis requires vitamin B6
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ALA synthase
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where is ALA synthase made?
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made in cytosol and transported into mitochondria
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Talk about the ALA synthase isoforms
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ALA synthase 1:
-ubiquitous-synthesized in liver and nucleated cells -repressed by heme Heme downregulates transcription, destabilizes mRNA and blocks translocation of precursor protein into mitochondria by binding to N-terminal mitochondrial targeting domain preventing uptake of proteins into mitochondria ALA synthase 2 -found in RBCS -regulated by erythropoietin and availability of intracellular iron |
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how is d-aminolevulinic acid transported out of mitochondria
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by small amino acid transporters
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Significance of ALA dehydratase?
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has a zinc ion that can be replaced by lead leading to lead poisoning and acumulation of ALA
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what allows coproporphyrinogen 3 to be transported back into the mitochondria?
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ATP-binding cassettee
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what does protoporphyrinogen oxidase do?
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converts methylene bridges to methenyl bridges
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what doe ferrochelatase do?
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adds iron to protoporphyrin.....this is also inhibited by lead.....from a clinical standpoint, you won't get this far upstream for it to even matter
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what can tregger porphyrias
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smoking, infections, fasting, chemicals, drugs
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inheritance of porphyrias
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all autosomal dominant except congenital erythropoietic porphyria which is autosomal recessive
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Sx of porphyrias
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-purple color caused y pigments in urine, skin, bone, teetch, of some pts
-neurovisceral attacks -photosensitivity Sx will depend on where in pathway mutation has occured neuro signs: accumulation of ALA and PGB and/or decrease in Heme in cells and body fluids Photosensitivity: accumulation of porphyrins in skin and tissue with spontaneous oxidation of porphyrignogens to porphyrins |
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ALA will bind to what receptor if it accumulates
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GABA
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4 effects of light activation of porphyrins that build up in the heme synthesis pathway
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-mast cell degranulation
direct tissue damage complement activation matrix metalloproteinases ROS are made and they cause these effects |
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medical use of porphyrin rings
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-against tumors
-doctors will inject tumors with porphyrins and then expose to light to kill tumor via ROS |
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management of porphyria attacks
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-avoid sunlight
-ingest B-carotene -treat with hemin to repress ALA synthase.....also provides heme |
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purpose of hemin
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-blocks creation of intermediates that can't finish cycle and also creates heme
-blocks ALA synthase |
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Vampire legend?
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-thought to be porphyria cutanea tarda
-uroporphyrinogen decarboxylase sensitive to light so they only come out at night and the light causes disfiguration and hair growth -must drink blood to replace heme |
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X-linked sideroblastic anemia
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-Disfunction in ALA synthase 2 or defect of vitamin B6
-hypochromic and microcytic anemia |
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Phenobarbital
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increases ALA synthase activity.....in individuals with porphyrias, it will exascerbate their sx
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lead poisoning
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-inhibits ALA dehydratase and Ferrochelatase
Treat these patients by injecting hemin |
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what is the only known source of biological carbon monoxide
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heme oxygenase
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heme oxygenase
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converts heme to billiverdin and NADP and CO using NADPH
will be activated by heme and other compounds and stress |
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how often do rbcs turn over
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every 120 days
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heme degredation pathway
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Heme>>>>1>>>>Billiverdin>>>>>bilirubin
1)heme oxygenase 2)Biliverdin reductase HO1: inducible by soking, cytokines, hypoxia, heme, metalloporphyrins, stress, shock, NO, cAMP HO2: constitutively expressed |
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which enzyme in heme degredation pathway requires NADPH?
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both Heme oxygenase and biliverdin reductase require it
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where does the breakdown of heme to bilirubin occur?
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in RBC
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how is bilirubin transported in the blood
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by albumin because bilirubin is only slightly soluble
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what happens once bilirubin reaches liver
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-it complexes with ligandin and many other proteins which prevent efflux of filirubin
-it next is conjugated with Bilirubin-UDP glucuronyltransferase and glucaronic acid is added to make the bilirubin more soluble |
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Bacterial B-glucuronidases
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once conjugated bilirubin reaches the terminal ileum and large intestine, the glucuronides are removed by bacterial B-glucuronidases
-this produces urobilinogen which is colorless -urobilinogen is then oxidized to stercobilin and urobilin and these are then excreted into the feces |
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hyperbilirubinemias jaundice
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elevation of bilirubin in the plasma
-yellow color of skin, nail beds and sclerae -Hemolytic jaundice......Liver can't handle rbc lysis to this extent -hepatocellular jaundice: cirhossis, hepatis....decreased conjugation system as well so bile can't exit -obstructive jaundice: obstruction of bile duct....prevents bile from getting into fecal matter. |
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Crigler Najjar Syndrome
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-deficiency of bilirubin UDP-glucuronyl transferase
-autosomal recessive type 1:complete absence of gene -increase in unconjugated bilirubin kernicterus: accumulation of bilirubin in brain -fatal in first 15 months of life type 2 -partial deficiency |
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Gilbert Syndrome
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decreased activity of UDP-glucuronyl transferase
30% enzyme activity increase in unconjugated bilirubin autosomal dominant -symptoms often occur during times of stress, exertion, fasting, and infections, but the condition is otherwise usually asymptomatic |
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Dubin Johnson Syndrome
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-secretion from hepatocytes into bile affected
-autosomal recessive -usually asymptomatic increase in conjugated bilirubin |
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2 methods to determine bilirubin concentration
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1)
-use diazonium salt to measure conjugated bilirubin -add methanol now and both conjugated and non-conjugated will now react with salt Total-direct=unconjugated 2)can use light over patients skin which will read bilirubin levels since bilirubin is hydrophobic and will be in membrane |
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neonatal jaundice
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-low bilirubin glucuronyl transferase
-large number of RBC destroyed -unconjugated bilirubin accumulates in brain leading to kernicterus which is bilirubin toxicity .....to treat these patients, you would put them under a blue light so that pyrole rings can be broken down and excreted |
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when ligands bind to receptor of G-pro, what are they acting as?
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-Guanine nucleotide exchange proteins for Ga subunits which will facilitate GDP release and binding of GTP
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toxin for Gas
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cholera: keeps it active
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toxin for Gai
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pertussis: keeps it active
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regulators of G protein signaling
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family of proteins that interact with and stimulate the GTPase activity on the alpha subunit
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Gaq effector enzyme
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phospholipase CB activation
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Small GTP binding proteins: 5 examples
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-are involved in controlling a diverse set of essential cellular functions
RAS: growth and differentiation Rho: integrin activity, Actin, NADPH oxidase Rab: vesicle transport ARF: vesicle transport and stimulation of PLD Ran: nucleocytoplasmic transport |
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talk about ras pathway
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Ras bound to GDP is inactive
-needs GEP to go from GDP>GTP ...it will now serve its function -two proteins controlling GDP binding are GDS (guanine dinucleotide stimulatory protein and GDI (Guanine dinucleotide inhibitory protein) |
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g protein coupled receptors are also known as....
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7 transmembrane receptors
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talk about g protein intracellular loops
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-has 3 loops on inside and these have concensus sequence that recognizes the g-protein....phosporylation of these sequences will uncouple the receptor from the g-protein.....this is a mechanism of desensitization
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G-protein coupled effector enzyme mechanism
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1) ligand binds
2) causes Ga currently bound to gdp to now be bound to gtp 3) this allows Ga to diffuse away from B and G units of G protein 4) Ga w/ atp bound will now activate AC causing it to convert ATP for cAMP 5) cAMP will now activate various kinases to cause effects |
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how does cholera work?
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it converts NAD+ to nicotinate and in doing so it will activate Gas subunit
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talk about PKA
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-has 2 regulatory subunits with binding sites for cAMP and 2 catalytic subuntis
-is inactive without camp bound because regulatory sites block catalytic sites. -when camp binds to regulatory site, it changes conformation opening access for catalytic site and causing cellular response by phosporylating many proteins |
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serine threonine kinases are generally what?
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cAMP dependent response
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tyrosine kinases are generally what
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insulin receptor response
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what does phosphorylation do to a protein
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changes its conformation and makes it more or less active
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phosphoinositide cascade
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-hormone binds activating causing g protein to now be bound to gtp
-this diffuses accross the membrane and now will activate Phospholipase C which will cleave PIP2 into IP3 and DAG. -IP3 will cause calcium release from ER, activation of PKC via calcium and Ca/calmodulin kinase response -DAG will activate PKC (DAG will remain bound to the membrane |
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all isoforms of PKC require what?
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phosphatidylserine for activation
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Lithium
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inhibits stepwise removal of phosphates from IP3 to from inositol (this process generally turns off the signal)
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turning off phospoinositide cascade
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-DAG is removed by diglyceride lipase
-IP3 is metabolized by stepwise removal of phosphates to form inositol. Lithium inhibits -Calcium is removed by Calmodulin/kinase activated pump |
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Tyrosine Kinase receptor
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-hormone binding to external domain activate tyrosine kinase activity of intracellular domain leading to various responses.
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Protein domains involved in insulin signalling
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L446
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MAPK cascade
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L447
-increases gene transcription |
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SH2 domain
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found on Grb2 and will bind to P-Tyr of IRS-1 in MAPK pathway
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insulin stimulation of glycogen synthesis
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448
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GF pathway
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449
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which hormones bind to JAK-STAT receptors?
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GH
interferons prolactin cytokines |
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talk about JAK-STAT receptors
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-lack endogenous tyrosine kinase
-upon ligand binding, receptors dimerize and noncovalently associate with JAK tyrosine kinase which become phosphorylated by the dimerization -STAT associates with the JAK-P and now is Phosphorylated itself -STAT now dimerizes, diffuses to nucleus and binds to DNA elements and regulates transcription Jack also phosphorylates tyrosines on receptors causing other SH2 domain containing proteins to be recruited and other pathways to ensue: ......ie.......MAPK, PLC, etc. pg 450 |
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Basic structure of purine and pyrimidines w/ numbering
structure of 5 nucleotides |
455
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syn and anti conformation
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Purine: syn and anti
pyrimidine: only anti |
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modified purines and pyrimidines are abundent in what?
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tRNA
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hypoxanthine structure
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456
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n7-methylguanine
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-molecular sensor for initiation of protein synthesis
-present at 5' terminus of most mRNA -control stability of mRNA |
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adenine preferred form
thymine prefferred form |
adenine: amino over imino
Thymine: keto over enol |
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enol form of T significance
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can lead to mispairing
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nucleosides
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only contain base and sugar
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what will happen when purines switch from anti to syn conformation in DNA?
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right handed helix as in B-DNA will turn into a Left handed helix as in Z-DNA
Z-DNA will be much more unstable |
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basic nucleotide structure
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458
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where can phosphates be attached in nucleotides?
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5'
2' 3' 2' and 3'....not possible for DNA formation |
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Orotic acid structure and Xanthine structure
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460
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source of atoms in the purine ring
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461
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first step in de novo purine synthesis
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PRPP synthetase using ATP (phosophoribosylpyrophosphate)
-461 inorganic phosphate activates the reaction and IMP, AMP, and GMP will inhibit it |
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committed step in purine synthesis pway
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formation of 5-phosphoribosyl-1-amine by using glutamine/PRPP amidotransferase
inhibited by IMP, AMP and GMP -reaction can also be controllwed by levels of PRPP and Glutamine -461 |
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importance of glutamine analogs
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since glutamine is needed for committed step in purine synthesis, it will be inhibited by glutamine antagonists such as azaserine and DON
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azaserine
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glutamine antagonist that can block purine synthesis pway
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DON
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glutamine antagonist that can block purine synthesis pway
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how is Gln-PRPP amidotransferase regulated by activation and inhibition
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-enzyme changes between an active monomer and an inactive dimer
activated by: PrPP inactivated by: IMP, GMP, and AMP |
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key points of 5-ribosylamine to IMP
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-requires much ATP and because of this salvage pathway is preferred
-requires THF for carbon |
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aminopterin
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inhibitor of THF synthesis which in turn prevents synthesis of IMP leading to purines.....does this by acting as competitive inhibitor to prevent dihydrofolate reducatse activity
----methotrexate does the same thing -----sulfa and trimethoprim only inhibit bacterial folate synthesis |
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what allows folate to go to THF?
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NADPH donating hydrogens
-needs serine to donate carbon atom uses dihydrofolate reductase |
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sulfa
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-competitively inhibit folic acid synthesis in bacteria thus limiting purine synthesis in bacteria
-humans do not synthesize folic acid |
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trimethoprim
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inhibits di-hydrofolate reductase thus inhibiting THF creation and in turn it will prevent synthesis of purines
-has much higher affinity for bacterial sx......need much greater amounts for it to affect mamalian sx |
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AICAR
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-intermediate in IMP creation
-prior to receiving carbon from THF -acts as potent activator of AMP kinase which acts as metabolic sensor regulating lipid and glucose metabolism to maintain energy homeostasis and protect against metabolic stress |
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what is purine deficiency primarily due to?
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deficiency in folic acid
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where is de novo purine synthesis mechanism found?
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liver is major site of synthesis
RBCs and WBCs cannot synthesize 5-phosphoribosylamine (they lack PRPP/glutamine aminotransferase) and therefore must rely on salvage pway for their supply...... |
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important point of bacteria purine synthesis
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-each step from 5-phoshoribosyl amine to IMP requires a separate enzyme
In Eukaryotes, the activities all reside on 1 enzyme.....this allows for no diffusion of intermediates and thus, better coordinated de novo synthesis of IMP |
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IMP to conclusion pathway
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463
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talk about GTP and ATP and importance in purine synthesis
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GTP provides energy for AMP synthesis
ATP provides energy for GMP synthesis |
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regulation of purine nucleotide synthesis scheme
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464
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basic overview of pyrimidine biosynthesis
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-synthesized as orotic acid
-orotic aci reacts with PRPP to form OMP -OMP is decarboxylated to UMP -UMP>UDP>UTP followed by UTP>CTP |
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carbon source for pyrimidines
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1,,4,5,6 from aspartate
2 carbon from bi carb 3 N from glutamine bicarb + amonium from glutamine +2 ATP>>>>>>carbamoyl phosphate see page 465 |
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Carbamoyl phosphate synthase 1 vs CPS2
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1: mitochondria urea cycle
2: cytosol orotate synthesis |
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is CAD in prokaryotes
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no only in eukaryotes
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pyrimidine nucleotide synthesis pway
and regulation in pro and euk |
465
1) CAD is composed of -CPS2 -ATC -DHO these catalyze the first 3 steps in pway 2)Dihydro-orotate dehydrogenase: orotic acid to dihydroorotate with use of NAD+.....located on mitochondrial membrane.....all other enzymes are cytosolic 3) orotic acid reacts with PRPP to form OMP....enzyme is orotate phosphoribosyl transferase 4)OMP>UMP using OMP decarboxylase *******O-PRT and OMP decarboxylase are part of multifunctional enzyme called UMP synthase 5) UMP>UTP requires 2 ATPs 6)CTP synthetase: converts UTP to CTP ....CTP inhibits enzyme ....GTP activates enzyme Regulation Pro: ATC is regulated step ...inhibited by CTP ...activated by ATP Euk: CPS2 is regulated step ..activated by ATP and PRPP ....inhibited by UTP and CTP |
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is CMP ever made by denovo synthesis?
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no.....it is convereted from UTP directly to CTP
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what inhibits OMP decarboxylase
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UMP and CMP
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orotic aciduria
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-deficiency in UMP synthase which involves 2 enzymes
1)orotate-phosphoribosyl transferase 2)OMP decarboxylase -leads to orotic acid build up and excretion -abnormal growth and megablastic anemia which is not corrected by giving B12 or folic acid -Uridine rich diet alleviates anemia and decreases orotate accumulation/excretion...its does this by bypassing metabolic pathway and blocking CPS2 thus reducing orotic acid formation |
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mechanism for conversion of ribonucleotides to deoxyribonucleotides
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467-8......
1)enzyme is ribonucleotide reductase which is a multiprotein complex comprised of ribonucleotide reductase, thioredoxin and the flavoprotein thioredoxin reductase and NADPH 1)Thioredoxin serves as hydrogen donor.....i 2)it's disulfide bond will then get reduced by NADPH via thioredoxin reductase |
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To get to dTTP what common intermediate will you have to go through?
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CDP>dCDP>dCMP>dUMP or UDP>dUMP
Can use THF to go from dUMP to dTMP |
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what is rate limiting step in DNA synthesis?
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Ribonucleotide reductase
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