PChem Exam 3 – Flashcards
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Unlock answers| What is insulin? |
| -hormone produced by B cells in the pancreas -peptide (protein) hormone made of amino acids -central role in regulating energy utilization and metabolizing carbs, fats, and proteins |
| How was insulin discovered? |
| -scientists found that pancreatectomy caused diabetes in dogs, and labs isolated the substance required for normal glucose metabolism |
| What is the endocrine portion of the pancreas? |
| Islets of Langerhan. Where B cells are found. |
| What does glucagon do? |
| -increases liver glucose production via GNG and glycogenolysis -increases lipolysis in adipose tissue |
| What mediates the action of glucagon? |
| G-protein coupled receptors that signal via cAMP-dependent PKA |
| What does insulin do? |
| -increases glycogen synthesis and glucose oxidation via glycolysis and PDH in liver -increases lipogenesis and fatty acid synthase |
| Insulin biosynthesis |
| proinsulin folds, is stabilized by disulfide bonds. Has a C-peptide which is cleaved prior to secretion |
| What stimulates insulin secretion? |
| increased plasma [GLUCOSE!] |
| Signaling pathways of insulin secretion |
| Major stimulus is glucose, but also: -IP3 and DAG production resulting in Ca2+ released from ER stores -cAMP and cAMP-dependent PKA -influx of extracellular Ca2+ -mediated by Ca2+-dependent exocytosis of insulin-containing vesicles |
| Insulin receptor |
| -2 EC alpha subunits: bind insulin -2 IC beta subunits: intrinsic tyrosine kinase activity for insulin signaling |
| Insulin-sensitive tissues containing insulin receptors |
| liver, muscle, adipose tissue, some CNS |
| What happens to the B-subunit of the insulin receptor once insulin attaches? |
| it is autophosphorylated, and it phosphorylates IRS-1 (insulin receptor substrate protein) which activates PI3 kinase. As a result, you get 1. cell growth, 2. protein synthesis, 3. glucose transport |
| What action does insulin have when it binds to its receptor? |
| -remember, IRS1-4 activates PI3 kinase -PI3 kinase recruits GLUT4 (glucose transporter), which stimulates glucose transport -muscle and adipose tissue only -also activates MAP kinase to increase protein synthesis |
| GLUT4 |
| major insulin-dependent glucose transporter in muscle and fat cells |
| GLUT2 |
| -B cell glucose sensor for insulin secretion -transports glucose out of intestine, liver, and renal tubular epithelial cells |
| What does insulin do in the liver? |
| -main: decrease hepatic glucose production -increases: glycogen synthesis, glucose oxidation, and fatty acid synthesis -decreases: glycogenolysis, and GNG |
| What does insulin do in the muscle? |
| -stimulates glucose uptake and oxidation -increases GLUT4 translocation, glycolysis, PDH, amino acid uptake, and protein synthesis -activates glycogen synthase -inhibits protein degradation |
| What does insulin do in the adipose tissue? |
| -increases fat synthesis (lipogenesis) -inhibits fat mobilization (FFA release) -antilipolytic |
| How does insulin cause anti-lipolytic effects in adipose tissue? |
| -increases lipogenesis, glycolysis & alpha-glycerol-P -activates LPL to store FA's as TAGs -increases leptin production -inhibits hormone sensitive lipase (HSL) |
| What does insulin do in the brain/CNS? |
| -inhibits hunger and increases metabolic rate to avoid obesity via hypothalamus -brain may resist insulin, which would cause obesity |
| What is insulin resistance? |
| -reduced ability of insulin to produce its normal actions in its target tissues due to inadequate insulin secretion for the degree of insulin resistance |
| What is hyperinsulinemia? |
| pancreatic B cells increasing insulin secretion to compensate for insulin resistance |
| What issues is insulin resistance associated with? |
| obesity, diabetes, cardiovascular disease, hepatic lipidosis (cats), Cushing's disease (dogs, horses), other equine diseases |
| What causes insulin resistance? |
| *obesity*, endocrine disorders, stress/infection, PCOS (increased androgens and fat), lipotoxicity, inflammation, oxidative stress, and low adiponectin (insulin-secreting hormone) |
| What actions within tissues induce insulin resistance? |
| -fat accumulation (FFAs) increases DAG and activates a form of PKC which phosphorylates serines instead of tyrosines and thus reduces activity of the insulin receptor and IRS-1 -nuclear factor kappa B (NFKB) and Jun kinase (JNK1) also phosphorylate serine instead of tyrosine -TNF alpha expresses SOCS instead of IRS-1, which activates serine kinases |
| Obesity relating to insulin |
| -obesity is associated with insulin resistance and glucose intolerance (dogs) -B cell dysfunction and glucose intolerance (cats) -reversed by weight loss |
| Insulin resistance in insulin target tissues |
| -liver: more glucose production -muscle: less glucose and amino acid oxidation, less protein synthesis -adipose: low glucose and FA uptake, high lipolysis (more FFAs) -need tyrosine phosphatase to stop this! |
| What are the functions of adipose tissue? |
| -thermal and mechanical insulation -energy storage (TAG) and release (FFA) -endocrine function (makes hormones/cytokines) |
| Why is adipose tissue important in veterinary medicine? |
| obesity- causes: -insulin resistance--> diabetes -anesthesia complications -bleeding fat in surgery |
| White adipose tissue (WAT) vs Brown adipose tissue (BAT) |
| -WAT is subq and in visceral organs -BAT is in specific regions and produces heat |
| Besides being TAG storage, what else is important about adipose tissue? |
| -collagen to anchor adipocytes -well-vascularized, and lots of nerves -inflammatory cells (macrophages); TNFalpha and IL6 are significant |
| Number and size of adipocytes |
| -hyperplasia= increased number -hypertrophy= increased size -small= insulin sensitive (may protect against obesity effects) -large= insulin resistant, lipolytic, secrete less adiponectin and more MCP-1 |
| Major metabolic pathways in adipocytes |
| -GLUT4, insulin-->glycolysis-->TCA cycle -->citrate (also insulin)-->lipogenesis -insulin stimulates FA uptake via LDL and storage as TAG -glucagon stimulates lipolysis of TAG via HDL and release as FFAs (inhibited by insulin) |
| Minor metabolic pathways in adipocytes |
| -PEPCK and PK (for GNG) -glycogen synthesis |
| Endocrine functions of adipose tissue (hormones) |
| -leptin: food, energy -adiponectin: energy, insulin sensitivity -TNFalpha: insulin resistance, inflmmation -Interleukin6: lipi metab, insulin resis -MCP1: recruit macrophages |
| Leptin |
| -gene for obesity primarily expressed in adipose tissue -decreases food intake. no leptin=obesity -also: increases reproduction, required for neuroendocrine and immune function, blood vessel growth/wound healing, bone growth, ANS function |
| Leptin signaling |
-receptor is cytokine-like -signals via activate JAK and STAT -activates PI3kinase and IRS1 (like ins.) -SOCS is bad: causes leptin resistance |
| How is leptin production and secretion regulated? |
| -more fat, more leptin -large adipocytes produce more leptin -decreases without food, increases after food intake -insulin stimulates (via glucose), lactate decreases it |
| What does insulin do to pyruvate dehydrogenate phosphatase? |
| It's active, and converts pyruvate into acetylCoA instead of lactate |
| Adiponectin |
-low levels: obesity, insulin resistance, type 2 diabetes -lowers glucose, activates AMP kinase, increases fat oxidation, which reduces lipid content, has anti-inflammatory actions -increases insulin sensitivity -less in larger adipocytes |
| What is diabetes mellitus? |
| -inability to regulate blood glucose concentrations, due to insulin deficiency or insulin resistance -also high circulating glucagon secretion/levels causing higher glucose production, ketogenesis, & ketoacidosis |
| Two forms of diabetes mellitus |
| 1. Type 1: insulin dependent juvenile onset 2. Type 2: non-insulin dependent. Related to obesity (used to be just adults, now kids too) |
| Type 1 diabetes |
| -low/no pancreatic insulin (need outside source) -usually due to B-cell destruction or pancreatitis -genetic (common DB for dogs) -causes hyperglycemia->ketoacidosis->death |
| Type 2 diabetes |
| -defects: insulin resistance and B-cell dysfunction -insulin initially high, then decreases -pancreatic insulin levels low compared to plasma glucose levels -more common in cats |
| Obesity and diabetes in dogs and cats |
| -dogs: insulin deficient, glucose intolerance -cats: B-cell dysfunction (reversed with diet) and glucose intolerance -all due to obesity |
| Clinical signs of diabetes mellitus |
| hyperglycemia, glycosuria, polyuria, polydipsia, poly/hyperphagia, ketosis, hyperlipidemia, protein catabolism (muscle loss) |
| Biochemical basis of hyperglycemia in diabetes |
-increased glucose due to increased GNG -decreased uptake of glucose into insulin-sensitive tissue due to decreased GLUT4 translocation |
| Glycosuria related to diabetes mellitus |
| -DM=sugar in urine -when kidney reaches renal threshold for glucose resorption, it spills into urine -lower threshold in ruminants |
| Polyuria/Polydipsia relating to DB |
| -glucose in urine causes osmotic gradient -polydipsia (more drinking) is secondary to polyuria (more urinating) -regulated by the hypothalamus |
| Polyphagia/hyperphagia relating to DB |
| -caused by low insulin and leptin levels -low glucose going to tissues, so protein and fat are used for energy, so there is weight loss even though increased food consumption -low protein=negative nitrogen balance |
| How do you diagnose diabetes? |
| -clinical signs -measure hyperglycemia -measure insulin or C-peptide levels (type 1) -oral glucose tolerance tests (type 2) |
| High/low metabolisms in insulin deficiency |
-high ketogenesis/lipogenesis -high protein catabolism -decrease in glucose use |
| What is ketosis and how does it relate to diabetes? |
| -more lipolysis creates more AcetylCoA, causing more FFA going into the liver -ketogenesis due to low insulin/resistance and high glucagon -smell of acetone on breath |
| Diabetic Ketoacidosis |
| -ketone bodies->acidic, cause metabolic acidosis->depressed CNS centers->coma -more common in insulin deficiency than type 2 -glucagon, cortisol, epinephrine->imp |
| Hypoglycemia and its causes |
| -low plasma glucose causes: increased insulin in therapy, in B-cells, long fasting, severe infections -glucagon restores plasma [glucose] |
| Signs/symptoms of hypoglycemia |
| hunger, drowsiness, sweating, palpitations, car accidents, convulsions, coma, death -glucagon impairment with repeated bouts of hypoglycemia |
| How does the pancreas control the metabolic adaptations from the fasted to the fed state? |
| -increase insulin after high protein/carb meals (PS nerves, hormones also contribute) -decrease glucagon after high carb meal, increase glucagon after high protein meal |
| How does liver transition from glucose production to glucose uptake/storage from the fasted to the fed state? |
| -decreases glycogenolysis, GNG -increases glycogen synthesis, glycolysis, glucose into TCA cycle for oxidation and lipogenesis -this all is mediated by changes in insulin, glucagon |
| How does adipose tissue transition from fatty acid production to fatty acid uptake from chylomicrons and VLDLs |
| -increase glycolysis (to provide alphaglycerol-P for FFA esterification) -increase glucose uptake via GLUT4 transl. -inhibit lipolysis (inhit HSL) -activate LPL for FA uptake and lipogenesis |
| How does muscle transition from fasted to fed state? |
| -get energy from glucose in fed state vs from FA oxidation in fasted state -glycogen and protein are usually not used for energy (reserves) |
| What hormones are produced by the GI tract that are involved in food intake and metabolism? |
| GIP (duodenum), Ghrelin (stomach), GLP-1 (ileum) |
| Ghrelin |
| -stomach -excess causes hunger/weight gain -inhibited by nutrients and insulin in stomach |
| GLP-1 and GIP |
| -stimulate insulin secretion -GLP-1 inhhibits glucagon, increases B-cell proliferation, reduces B-cell apoptosis. Inactivated by DPP-IV |
| What is feline hepatic lipidosis? |
| -severe lipid (TAG) accumulation in the hepatocyte -aka hepatic steatosis, steatohepatitis, cirrhosis -risk factors: obesity, middle-aged, neutered |
| How is hepatic lipidosis diagnosed? |
| -anorexia, weight loss -jaundice, hepatomegaly, muscle wasting -liver enzymes, total bilirubin increased |
| Signs of protein depletion in feline hepatic lipidosis |
| muscle wasting, low serum albumin, increased blood clotting time, anemia, fatty liver |
| How do you prevent feline hepatic lipidosis? |
| -avoid prolonged fasting -monitor food intake/weight, especially during stressful times |
| How does energy use work when an animal starts running at a high speed? |
-begins with ATP (from muscle and from anaerobic glycolysis [glycogenolysis]) -then creatine phosphate (with ADP, becomes creatine and ATP) sustains exercise while transferring from anaerobic to aerobic |
| Creatine phosphate reaction details |
-enzyme: creatine phosphokinase (CPK) or creatine kinase (CK) -CPO formed when muscle is relaxed and doesn't need ATP, and also formed from ATP and creatine during exercise -CK/CPK shuttle phosphates to myosin filaments for contraction (so CPO is a source of high energy phosphates) |
| What provides the best energy for what type of workout? |
-Phosphocreatine: short bursts at max effort (s) -Anaerobic: intermediate duration intense effort (m) -Aerobic: long duration at reduced effort (hours)
|
| What happens to levels of energy sources during sustained exercise? |
-ATP decreases after seconds -C-PO3 decreases after that -Anaerobic glucose from glycogen decreases after minutes -then you get 30% aerobic glucose from glycogen (stable/decreases) and 60% aerobic FFAs increases during exercise after hours |
| How are energy sources for ATP production regulated? |
-glucose and FFA reserves, exercise intensity -liver uptakes less FFAs, so there are less ketone bodies -so, exercise reduces [TAG] and [KB], which is good for patients with triglyceridemic, ketoacidotic, and diabetics |
| How are energy sources for ATP production regulated hormonally? |
-activated by: glucagon, cortisol, epinephrine/NE, GH (levels increase during exercise-they also increase HSL) -inhibited by: insulin (decreases, bc glucose levels go down, which is caused by glucagon) |
| What are the health advantages of regular exercise for diabetics? |
-less glucose 6P neg feedback, so more glucose uptake -more AMP, causing lipolysis, glycogenolysis -more GLUT4 transporters in skeletal muscle -increases insulin sensitivity *insulin dose in diabetics should be reduced if they exercise |
| Why can some animals run and others can't? |
| -loss of mito, so no TCA cycle, B-oxidation, just anaerobic conversion of glycogen to lactic acid (ineffective for producing ATP, so occurs at high rate and thus causes fatigue) |
| What happens when oxygen becomes limiting during exercise? |
anaerobic glycolysis produces lactate, which via GNG, produces glucose for energy -inefficient, but produces energy rapidly in absence of oxygen |
| What limits the Vmax of oxygen consumption during exercise? |
-rate of O2 transport by circulation -oxygen diffusing capacity of lungs -oxygen utilization by muscle tissue** -note: VmaxO2 is when energy requirements exceeds max capacity for AErobic metabolism |
| What is the pattern of oxygen consumption during and after exercise? |
| -slowly rises as exercise begins and reaches a plateau (VmaxO2) -when exercise ends, O2 drops but not back to initial value (ventilation is still above resting value). Repays oxygen debt from exercise -drops back to starting rate multiple minutes after exercise stops |
| FOUR components of oxygen debt that must be repaid in recovery |
Major: -resynthesis of high energy phosphate bonds in ATP and C-PO -conversion of lactate to glucose in liver ; Minor: -decrease in O2 stored in blood ; muscle -removal/oxidation of lactate formed from pyruvate in anaerobic glycolysis *conditioned animals can reduce blood [lactate] and [H+], so pyruvate, and thus oxygen, utilization is better |
| What factors increase respiratory ventilation (hyperventilation)? |
| CNS, motor sensors, joint movement, muscle contraction, chemo sensors, O2 and CO2 levels, cardiac output, plasma pH levels |
| What are the benefits of conditioning for exercise? |
| -increase in VO2 (through aerobic training) -more blood sent to liver than muscles so liver can help with metabolic reparative process -increased capillary beds in muscle for exchange surface -more mito size/number allows more FA oxidation -increased insulin sensitivity -less lactate formed |
| What is the cardiovascular response to exercise? |
| -increased cardiac output and blood flow |
| How is adenosine related to exercise, and in this instance, how is it formed? |
| -vasodilator -myokinase (adenylyl kinase) forms ATP and AMP, and the AMP is deaminated to form IMP and NH4, or a phosphate is removed to form adenosine |
| Physiological benefits of training? |
| -increased aerobic capacity/cardiac output -muscle hypertrophy (inc. sarcomere) -inc. blood vessel/mito size -inc. glycogen storage capacity -inc. lactate, proton, tolerance |
| What happens during exercise for animals with a glycogen metabolism deficiency? |
| defective branching enzyme, so it takes longer to release glucose from glycogen -solve this by doing long-term, mild exercise, carb meals |
| What is inflammation? |
| a localized reaction to a foreign substance or pathogen gauged toward destruction, dilution, or an attempt to wall off the substance or pathogen |
| Components of inflammation |
1. promotion: triggered by pathogen, foreign material 2. responding cells that release signaling mediators: injured, mast, macrophage 3. mediators: interleukin, metabolites, ARACHIDONIC ACID 4. cell/organ response: swelling, pain, fever, secretion from epith. cells |
| Mediators of acute inflammation |
-prostaglandins: increase vasodilation and chemotaxis of leukocytes (movement of cell) -leukotrienes: increase vascular permeability and chemotaxis of leuks *responsible for inflammatory response |
| The eicosanoid cascade release of inflammatory mediators |
| stimulus->arachidonic acid-> leukotrienes, prostaglandins/thromboxanes, isoprostanes |
| What is the precursor for arachidonic acid? |
-Phosphatidylcholine (via Phospholipase A2) -Phosphatidylinositide + DAG (Phospholipase C ; DAG lipase) -thes are the only phospholipid precursors |
Mechanism of eicosanoid reaction aka arachidonic acid cascade |
-bind to G-protein coupled receptor to up or down regulate cAMP -local function (so for endocrine, does not travel long distance) |
| How are eicosanoids formed? |
-PGs via COX (cyclooxygenase) 1 and 2 (isoforms of Prostaglandin H synthase) -leukotrienes/lipoxins (5-HPETE-;LTA4-;LTB4 OR LTA4-;LTC4-;LTD4-;LTE4) via LOX (lipoxygenase) -epoxides (EETs) via cP450 epoxygenase (renal and cardiovascular effects) -isoprostanes via free radicals (potent vasoconstrictors) -diet(linoleic a.-;arac a.-;linolenic a.) -but arachidonic acid is precursor |
| How does lipoxin affect the anti-inflammatory pathway? |
| -competitive inhibition: binds the anti-inflammatory receptor |
| What inhibits the eicosanoids? |
-corticosteroids: inhib COX -benoxaprofen zileuton: inhib LOX -NSAIDs (aspirin): inhib COX |
| In ischemia/reperfusion, the extent of damage depends on what? |
| -type (full blockage vs. partial) -duration -severity (type of tissue, adaptability of tissue) *if apoptosis/necrosis occurs, irreversible |
| Tissues most susceptible to I/R damage |
| -brain -heart (rely heavily on aerobic metabolism) -occurs during stroke, birth, hibernation |
| Etiology (cause) of I/R |
| -no/low oxygen or substrate availability -due to: metabolites, substrate depletion, pH paradox, osmolarity issues, immune response |
| Relationship between oxygen, mitochondria, and neuronal function |
-mitochondria need O2 to function, neurons need mitochondria to survive. oxygen drives oxidative phosphorylations, so without O2, no/low ATP -ischemia/anoxia causes encephalophathy-;brain damage (ex. dystocia) |
| What do lack of oxygen and substrates as a result of I/R lead to? |
| -ATP depletion -mito/membrane/DNA damage -altered ion concentrations (affecting the pumps) -active proteases, phospholipases -inact. of enzymes -proteolysis of cytoskeleton -detachment of ribosomes -increased ROS production (only thing that happens during R) |
| How does oxygen availability affect Na/K pump? |
| pump driven by energy stored in ATP molecules made in mito by oxidative phosphorylation, which is dependent on oxygen |
| How is pH altered by I/R? |
| -increased ANaerobic glycolysis causes increased lactic acid production->low pH (acidosis). -increases Na/H exchanger, so influx of Na into cell, which causes influx of Ca, causing contractile dysfunction |
| What causes excessive Calcium entry into the cell? |
Excessive glutamate release, which causes excecss intraceullular calcium, lactate dehydrogenase (LDH) -IM calcium activates proteases and phospholipases (membrane damage), cellular endonucleases (cause cell death), and ATPases (lower ATP) |
| What proteases cross the blood-brain barrier with I/R? |
| -MMP13, MMP9, MMP2 or gelatinase |
| THREE phases of resuscitation after cardiac arrest |
-electrical (0-4m): no flow -circulatory (4-10m): CPR, low flow -metabolic (;10m): post-CPR |
| What are the worst ROS and what are the sources of ROS? |
OH- and ONOO- are worst -sources: mito ETC- complex I and III, xanthine oxidase, activated neutrophils, inflammation |
| What happens to ATP in I/R? |
| broken down to xanthane, and xanthane oxidase converts it and oxygen to superoxide and uric acid |
| What is the 'no reflow phenomenon'? |
| -blocked capillaries from reperfusion -due to eicosanoids and superoxide adhesing leukocytes and platelets to vessel walls -also due to ROS dislodging plaques |
| What effects do ROS have? |
| mito function/DNA synthesis inhib, enzyme inhib/activ, organ dysfunction, phospholipid oxidation, protein nitration, apoptosis |
| What are the cells defenses against ROS? |
-enzymatic (SOD, catalase, GPX) -nonenzymatic (vitamins A,C,E, glutathione, metal-binding proteins) |
| What is the significance of N-acetylcysteine? What other things do the same? |
| -it prevents edema -it's a precursor to glutathione -others: calcium-channel blockers, plasmic as a thrombolytic agent, sodium-channel blockers, tetracyclines |
| Details of nitrogenous compounds |
| -no storage form of these molecules -polymeric forms have functional roles in cells -they constantly turnover, esp proteins and mRNA -major source is diet (proteins, nucleic acids) -degradation forms toxic compounds, said degradation has specific pathways -amount/form of N in plasma is diagnostic (BUN, [ammonia]) |
| Types of Nitrogen Balance |
1. Neutral: intake of N=loss (norm for adults) 2. Negative: intake<loss (starving/diseased animals) 3. Positive: intake>loss (growing animals) |
| Ways excess Nitrogen is excreted |
| 1. ammonia (ex. aquatic animals) 2. urea (ex. all mammals) 3. uric acid (ex. birds, reptiles) |
| What is the most common ammonia carrier? |
-glutamate (glutamate dehydrogenase), glutamine (gluatmine synthetase), & carbamoyl-P (carbamoyl phosphate synthetase)
-uses ATP to get glut. via GDH and glutamine synthetase, OR transaminase |
| What reactions free ammonia for excretion (if in kidney) or formation into urea (if in liver)? |
| -glutamine to glutamate via glutaminase -glutamate to alpha-KG via GDH |
| What cofactor do transaminases require? |
-Pyridoxal phosphate (active VitB6) -have a -HC=O group |
| Transamination |
-moving amino group from one aa to another compound to create another aa -donor: glutamate, sometimes aspartate -ex of rxns: glutamate pyruvate transaminase (SGPT-transfers aa's from muscle to liver, product=Ala), glutamate oxaloacetate transaminase (SGOT-imp for mal/OAA/asp shutle in GNG, product=Asp) |
| Urea cycle |
| -produces excretory product to remove excess N -high in liver, low in brain, kidney -mito (2 ATPs) and cytosol (1 ATP) -not in aquatics, birds, reptiles |
| Control points in the urea cycle |
-CO2+NH4+2ATP=;carbamoyl-P+2ADP+PO4 via carbamoyl phosphate synthetase I (mito) -N-acetyl glutamate is regulator for 1st step -Arg+H2O-;ornithine+urea via ARG1 |
| How is urea formed? |
-2 amino groups (1 from NH4, 1 from Asp) -carbon from HCO3 -ornithine is the carrier -urea precursors: free NH3 and aspartic acid |
| Key points about urea cycle |
-ornithine can enter mito for 're-use' -fumarate can go to TCA cycle |
| Controls of the urea cycle |
1.[ammonia]: higher-; get rid of it. make CP with CPS1 enzyme 2.allosteric control of CPS1 (need N-acetyl glutamate [which needs arginine]to activate) 3. [ornithine]: low conc.=low urea prod. produced from arginine ; glutamate 4. enzyme levels: up w/protein, starvation |
| Levels of which molecules are most important for the urea cycle? |
| -ammonia -arginine -ornithine |
| What is hepatic encephalopathy? |
| loss of hepatic cells from congenital defect, infection, or toxic substances results in increased levels of ammonia in blood. causes CNS toxicity: ATP taken from TCA cycle because GDH and glutamine synthetase take alpha-ketoglutarate from cycle |
| Details of urea cycle relating to the kidney |
| -low levels: CPS1, ornithine transcarbamoylase, arginase -extracts citrulline from blood, releases Arg into blood to provide maint. level of Arg. -arginine in kidney not made by arginase like it is in the liver |
| What is the structure of an amino acid? |
| amino group, hydrogen, R group, carboxyl |
| Details of protein degradation |
-per day, 3% degraded into amino acid pool (which is 1% TP) -degradation=synthesis -1/3 AA pool used for biosynthesis -rest used for: fat, glucose, energy (glucogenic-majority, and ketogenic) |
| What is the importance of a proteasome? |
| -disposes aged proteins that are ubiquitin-tagged. unfolds and transports protein to proteolytic core. peptide fragments used for AAs |
| What happens to proteins and amino acids from digestion? |
| protein->polypep+AA->oligopep+AA->AA via enzymes (cut at dif points within protein) in stomach, pancreas, small intestine. portal vein has free AAs post-meal. The AAs go to the liver |
| Transport of amino acids into cells |
-[AA] extracell-low, [AA] in cell-high -active transport, consumes ATP - |
| Removal of Nitrogen from amino acids |
-1st step to produce energy from AA -N protects AA from oxidative breakdown -1st catabolism step: transamination (N from AA to alpha-KG to form Glutamate). catalyzed by aminotransferases |
| What does transamination in the amino acid involve? |
| move the amino group from alpha-amino acid to alpha-ketoglutarate to form glutamate via aminotransferase |
| What are the two most important aminotransferases? |
-alanine aminotransferase: produces glutamate (collects N) -aspartate aminotransferase: produces apartate (for urea cycle) -can supply OR degrade AAs: equilib=1 -they require VitB6 (pyridoxal-P) as cofactor** |
| Deamination of Glutamate |
| -glutamate dehydrogenase (GDH) -produces ammonia, NADH, A-ketoglutarate. NADH makes 3 ATPs, A-ketoG goes into TCA cycle (more energy) |
| Glutamate dehydrogenase (GDH) |
| -equilib is reversible: dispose (when [AA] high, energy low) or synthesizes {when [AA] low, energy high) amino acids |
| What are the two major systems for moving ammonia to the liver? |
| -glutamine synthetase system (ammonia+glutamate=glutamine to liver->lose 2N to urea cycle) -glucose-alanine cycle (glutamate->alanine to liver->lose NH3 to A-KG->glutamate+pyruvate->GNG to glucose then back to pyruvate to become an amino recipient) |
| Nitrogen flow from protein to urea |
| -AA's transaminated to glutamate -GDH makes ammonia (mito) for urea cycle -glutamate transaminated to aspartate (cytoplasm) for urea cycle |
| What happens to the amino acids after Nitrogen is removed from them? |
| -glucogenic: form glucose, glycogen (majority) -ketogenic: make fat, cholesterol |
| Cystinuria (cystine stones) |
| -male dogs -transporter defect-> high cystine (aa) in urine->precipitates to form stones -treat with low protein diet |
| Melamine toxicity to the kidney |
| -pet food scare '07 -increases nitrogen in pet food and cows milk -melamine and cyanuric acid (not aa's, but are nitrogenous compounds) form a crystal which damages promixal tubules |
| Liver-portosystemic vascular shunt |
| -portal blood bypasses liver and is not delivered to it, so avoids amino acid catabolism and urea cycle -causes hepatic encephalopathy, high ammonia, and neuro issues (usually seen after high protein meal) -surgery to repair shunt, put animal on low-protein meals, antibiotics for bacteria |
| Aminotransferases as marker enzymes of liver damage |
| -intracellular, so when liver is damaged, released to circulation, and levels rise, which diagnoses liver damage -ex: eating hepatotoxic mushroom (ALT AND Bilirubin values rise) |
| Tests for renal disease are Blood Urea Nitrogen and Creatinine- why? |
| -urea is filtered by kidney, so diseased kidney creates high BUN values (as does protein diet), while liver disease decreases -ruminants have low BUN (veggie diet) -kidney also filters creatinine, so high creatinine means decreased kidney function |
| Porphyrins |
| -synthesized from amino acids -four pyrrole rings with side chains -centered iron, four nitrogrens -uncolored: nonplanar, colored: planar |
| Examples of Porphyrins |
| -hemoglobin: transports oxygen -myoglobin: delivers O2 to muscle -cytochromes: transport electrons -catalase: catabolizes H2O2 |
| Why is a heme important? |
| transports O2 and electrons, detoxifies drugs, protects from oxidative stress |
| Heme biosynthesis |
| -by the cell because heme is reactive -sites: bone marrow, liver -1st step: Succinyl-Coa (w/ALA synthase) in mitochondria, then goes to cytosol, then back to mito |
| Regulation of Porphyrin metabolism |
| 1. end-product feedback- heme inhibits Ala synthase 2. translational- heme levels must match globin levels |
| Lead poisoning and Porphyrins |
| -lead inhibits Ala-dehydrase (and thus heme synthesis) -causes anemia, demyelinating neuropathy -diagnosis: ALA in blood, urine, Pb in blood, urine, tissues -treat with lavage and lead chelating agents |
| Porphyria and porphyrins |
| -genetic defect in biosynthetic enzymes (though not Ala synthase) causing buildup of toxic porphyrin intermediates and produces toxic ROS -aggravated by steroid use -exposure to sunlight, colored/fluorescent teeth, colored urine, skin lesions, high urine/blood Ala -treatment: no sunlight, hemin injections to inhibit Ala synthase, beta carotene to scavenge ROS |
| Heme catabolism |
| -RBCs last 120 days in circulation -degradation: heme->biliverdin (green, via heme oxygenase)->bilirubin (yellow, via biliverdin reductase). -bilirubin is toxic, so goes to liver attached to albumin, and secreted in bile. makes feces brown and urine yellow |
| Jaundice/Icterus |
| -increased bilirubin, yellow skin/eye |
| Time course of a bruise |
| 1. red- oxygenated blood to trauma space 2. blue- deoxygenated hemoglobin 3. green- macrophage with heme oxygenase degrade heme 4. yellow- digestion by biliverdin reductase in macrophages |
