FORM & FUNCTION (AA Metabolism) Flashcards
Protein structure:
-primary structure: AA residues
-secondary structure (alpha-helix, beta-sheet)
-tertiary structure (polypeptide chain)
-quaternary structure (assembled subunits, dictates the function)
*digestion or muscle breakdown (starvation)
*protein contributes to 10-15% of energy
Amino acids:
-20 AA
>9 essential (dietary only)
>11 non-essential (synthesized by body)
-can be both an acid or base depending on the R group
Components of an AA:
-side chain
-amino group
-carboxyl group (proton donor)
AA catabolism:
- Ingested protein (stomach)
- Polypeptides (small intestine)
- Amino acids (small intestine)
- Amino acids (serum – most goes to the liver)
AA catabolism location:
-liver governs distribution of AA (like an airport)
-most AA are catabolized in the liver except:
>BCAA (skeletal muscles)
>Gln (intestine, kidney)
>Val (brain)
AA pool:
- Building blocks to synthesize new tissue proteins
- Forming non-protein cellular molecules (ex. NTs)
- Generates intermediates to feed into other energy pathways (via alpha-keto acids)
*excess AA cannot be stored
*will likely end up as fat molecules
Goal of excess AA breakdown:
-to form alpha-keto acids (energy precursors)
>gluconeogenesis
>lipogenesis
>ketogenesis
Alpha-keto acids:
-requires the removal of alpha-amino group (1st step of catabolism)
>alpha-ketoglutarate acts as an acceptor of the alpha-amino group
*transamination
Transamination:
-alpha-ketoglutarate accepts an alpha-amino group
-catalyzes by transaminases (aminotransferase)
-some require additional enzymes, but all end products are alpha-keto acids that form an energy metabolite
*get glutamate
Clinical relevance: aminotransferase:
-serum activity of aminotransferase used as an indicator of tissue damage
-enzyme is normally inside the tissue
*release into serum indicates tissue damage
Ex. ALT and AST
Alanine transaminase (ALT):
-alanine to pyruvate
-found in kidney, heart, muscle and liver (very high)
-high levels (>2-3 fold increase) indicate liver damage in cats and dogs
*not used in large animals (low ALT activity in liver)
Aspartate transaminase (AST):
-aspartate to oxaloacetate
-found in liver, RBC, heart, skeletal muscle (highest conc.)
-high levels indicate possible muscle trauma (rhabdomyolysis) OR liver disease
Fate of Glutamate:
-universal end product of transamination
-processed in the liver
-De/transaminated to recycle alpha-ketoglutarate
-NH4+ enters the urea cycle
NH+ enters the urea cycle:
-important step to remove toxic nitrogenous waste (renal section)
*nitrogen are toxic in high amounts
AA acid substrates for CAC:
-acetyl-CoA is NOT glucogenic
>1 oxaloacetate is required to form citrate
*this mechanism is critical for starvation survival
Glucogenic AA:
-form oxaloacetate to enter gluconeogenesis
Ketogenic AA:
-form acetyl-CoA or acetoacetyl-CoA
Non protein derivatives:
-tyrosine derivatives
-glutamate derivatives
Tyrosine derivatives:
-catecholamines
-Thyroid hormones
Catecholamines:
-amine containing catechol (neurotransmitter & hormone)
Ex. dopamine, E and NE
Dopamine:
-NT
-regulates motor movement
NE and E:
-NT and hormone
-produced by adrenal cortex
-regulates flight-or-flight response
-acts on alpha and beta receptors to stimulate CNS
Thyroid hormones examples:
-tetraiodothyronine (T4)
-triiodothyronine (T3)
Thyroid hormones:
-2x tyrosine + iodine molecules
-iodine from diet (iodized salt, seafood, dairy)
-every cell requires thyroid hormones to regulate metabolism
*hypothyroidism (endocrine disease) linked to obesity
Glutamate derivatives:
-glutamate is a universal produced when alpha-ketoglutarate is broken down
-GABA: gamma-aminobutyric acid
*major inhibitory NT in the CNS
>reduces neuronal excitability/block nerve impulses
GABA as NT:
- Released from presynaptic neuron
- Binds to postsynaptic neuron
- Cl- enters postsynaptic neuron
-negative charge causes inhibitory post synaptic potential=*inhibits nerve impulse
>hyperpolarisation
Sedatives:
-enhance GABA effects
Examples:
-benzodiazepine
-zolpidem (Ambien)
Glutamate as NT:
-serves as an excitatory NT
1. Released from presynaptic neuron
2. Binds to postsynaptic neuron
3. Na+ enters postsynaptic neuron
-positive charge causes excitatory post synaptic potential
>depolarisation
GABA Clinical Relevance: Epilepsy
-epilepsy: over stimulation/excitation
-excess glutamate (depolarization) or inadequate GABA (hyperpolarization)
-over-excitation of neuronal activity
Therapeutic: GABA agonists:
-phenobarbital
-benzodiazepine
Ivermectine: (GABA related drugs)
-in parasite control
-broad spectrum: heartworm, lice, scabies (nematodes and arthropod)
-triggers paralysis in parasites (enhance inhibitory NT)
-low toxicity in mammals
*in mammals, removed by a drug pump called MDR1, does not cross BBB
GABA neurons (ivermectine):
-mammals: located in CNS
-arthropods & nematodes: PNS
MDR1:
-multiple drug resistance 1
Ivermectin sensitivity: clinical signs
-most commonly ataxia or depression
-cattle: 20-40x the therapeutic dose (TD)
-horses: 10x TD
-pigs: 100x TD
-dogs! Collies: 15-30x the therapeutic dose
>beagles: greater than 200x TD
Collies:
-70% frequency have the MDR1 mutation
