PChem Exam 3

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
major insulin-dependent glucose transporter in muscle and fat cells
-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)
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
-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

-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
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)
-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?
-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)
-severity (type of tissue, adaptability of tissue)
*if apoptosis/necrosis occurs, irreversible
Tissues most susceptible to I/R damage
(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


-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?
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)


-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
-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
-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

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