#9: AAs as Biosynthetic Precursors & AA Metabolic Diseases

When the degradation of Tyrosine is inhibited, Homogentisate accumulates and is excreted as urine where, upon oxidation, turns black

Alkaptonuria (“Black Urine Disease”)

Patients with Alkaptonuria are prone to developing _______

arthritis

Name the term coined by Sir Achibald Garrod (1902) who recognized the link between metabolic disease and genetics

Inborn Errors of Metabolism

Which disease did Sir Achibald Garrod (1902) first describe?

Alkaptonuria (“Black Urine Disease”)

Alkaptonuria (“Black Urine Disease”) is due to a __________ in the ________ responsible for breaking down _______________ (________________ _________________).

deficiency, enzyme, Homogentisate, Homogentisate 1,2-Dioxygenase

Tyrosine Synthesis:

• Reactants: _____________, _____

• Enzyme: _______________ _____________

• Products: __________, _____, ______

phenylalanine, NADH, Phenylalanine Hydroxylase, tyrosine, H2O, NAD+

Tyrosine Breakdown:

• Reactant: ___________

• Intermediate: ______________

• Products: __________, __________

tyrosine, homogentisate, fumarate, acetoacetate

Name the 2 processes that make up “Phenylalanine breakdown”

Tyrosine synthesis, Tyrosine breakdown

What is this a picture of?

phenylalanine

What is this a picture of?

tyrosine

What is this a picture of?

homogentisate

Genetic defect in Phenylalanine Hydroxylase (liver) causing phenylalanine to accumulate, which activates an alternative pathway; produces buildup of phenylalanine, phenylpyruvate, and phenyllactate in the blood, tissues, and urine.

Phenylketonuria (PKU)

A genetic defect in which enzyme causes Phenylketonuria (PKU)?

Phenylalanine Hydroxylase

Phenylketonuria (PKU) Alternative Pathway

• Reactants: ________________, __________

• Enzyme: _______________ _____________

• Cofactor: ______

• First Products: _________, ________________

• Second Product: _________________

phenylalanine, pyruvate, Phenylalanine Transaminase, PLP, alanine, phenylpyruvate, phenyllactate

Which disease is very easy to detect by testing the urine?

Phenylketonuria (PKU)

Which disease leads to severely impaired brain development, which is why newborns are frequently screened for it?

Phenylketonuria (PKU)

What is the treatment for newborns with Phenylketonuria (PKU)?

low-protein diet

What is this a picture of?

phenylpyruvate

What is this a picture of?

phenyllactate

Where does Tyrosine Synthesis & Phenylalanine/Tyrosine Breakdown occur?

liver, kidneys

What is the amino acid precursor for the bioactive amine Dopamine?

tyrosine

What is the amino acid precursor for the bioactive amine Norepinephrine?

tyrosine

What is the amino acid precursor for the bioactive amine Epinephrine?

tyrosine

Tyrosine — Bioactive Amine Synthesis

• Reactant: ___________

• Enzyme: ____________ _______________

• Intermediates: __________, ______

• Enzyme: ___________ ____ _____________

• Cofactor: _______

• First Product: _______________

• Enzyme: ______________ _____-_____________

• Second Product: ___________________

• Enzyme: ______________________ ___________ _________________

• Cofactor: ________

• Final Product: _____________________

tyrosine, Tyrosine Hydroxylase, L-Dopa, CO2, Aromatic AA Decarboxylase, PLP, dopamine, Dopamine beta-Hydroxylase, norepinephrine, Phenylethanolamine N-methyl Transferase, SAM, epinephrine

________________ = increase heart rate, blood pressure, stimulate an increase in blood glucose, neuromodulators

Catecholamines

What are 3 examples of Catecholamines?

dopamine, norepinephrine, epinephrine

Which bioactive amine is responsible for triggering our “fight or flight” response?

Which amino acid is its precursor?

epinephrine, tyrosine

What is this a picture of?

L-Dopa

What is this a picture of?

dopamine

What is this a picture of?

norepinephrine

What is this a picture of?

epinephrine

In the central nervous system (CNS): dopamine is a _______________

neurotransmitter

Outside the CNS: dopamine functions as a ________ __________

chemical messenger

Name the bioactive amine that inside the CNS is associated with motor control, reward-motivated behavior, and hormone release

dopamine

Name the bioactive amine that outside the CNS is associated with blood pressure, kidney function, intestinal motility, and insulin release

dopamine

When the neurons responsible for producing neurotransmitters like dopamine in the substantia nigra are dying, leading to a dopamine deficiency in the brain (CNS)

Parkinson’s disease

Parkinson’s Disease is associated with a deficiency of _____________

dopamine

In order to treat Parkinson’s Disease, we need to increase ____________ levels in the _______. To do this we give 2 things: _________ and _____________.

dopamine, brain, L-Dopa, carbidopa

drug that inhibits the Aromatic Amino Acid Decarboxylase that produces dopamine

carbidopa

Which enzyme involved in dopamine synthesis does carbidopa inhibit?

Aromatic AA Decarboxylase

Can dopamine cross the blood/brain barrier?

no

Can L-Dopa cross the blood/brain barrier?

yes

Can carbidopa cross the blood/brain barrier?

no

True or False: dopamine is easily degraded in circulation

true

Why inhibit the Aromatic AA Decarboxylase with Carbidopa? → L-Dopa is rapidly decarboxylated by Aromatic AA Decarboxylase in the ________ and other sites to form _________. High levels of circulating __________ have bad side effects (______). CarbiDOPA cannot _____ the _____/_____ ________ so it only inhibits ________ production _________ the CNS leading to fewer side effects and more L-Dopa reaching the _____ since it isn’t being used to make _________ outside the brain. 

intestine, dopamine, dopamine, nausea, cross, blood/brain barrier, dopamine, outside, brain, dopamine

Why L-Dopa instead of Dopamine for Parkinson’s Disease? → L-Dopa can _____ the _____/____ _______ in order to reach the _____ while dopamine cannot and is __________ in the circulation

cross, blood/brain barrier, brain, degraded

What is it about carbidopa’s structure that prevents the synthesis of dopamine?

Hydrazine group forms Schiff’s Base with PLP and gets stuck because the extra nitrogen prevents the resonance-stabilized carbanion from forming

___________ ___________ = a drug that inhibits a biological process by becoming covalently bonded to an enzyme

Example: __________

suicide inhibitor, carbidopa

What is this a picture of?

carbidopa

What is the amino acid precursor for the bioactive amine Gamma-Aminobutyrate (GABA)?

glutamate

_________ = most common neurotransmitter; excites neurons

glutamate

_______ = inhibitory neurotransmitter

GABA

Glutamate — Bioactive Amine Synthesis

• Reactant: ___________

• Enzyme: ____________ _____________

• Products: ________, ______

glutamate, Glutamate Decarboxylase, GABA, Co2

What is this a picture of?

GABA (Gamma-Aminobutyrate)

What is the amino acid precursor for the bioactive amine Histamine?

histidine

_________ = vasodilator; allergic response

histamine

_________ (______________) = inhibits histamine response by binding to histamine receptor

Benadryl, Diphenhydramine

Histidine — Bioactive Amine Synthesis

• Reactant: ___________

• Enzyme: ____________ _____________

• Products: ____________, ______

histidine, Histidine Decarboxylase, histamine, CO2

What is this a picture of?

histamine

What is the amino acid precursor for the bioactive amine Serotonin?

tryptophan

Where is Serotonin found? (3)

intestine, platelets, CNS

When released into the intestine, _________ helps regulate gut movements

serotonin

When released by platelets at the site of blood clots, __________ acts as a vasoconstrictor and helps stop bleeding

serotonin

When released in the CNS by serotonergic neurons, _________ can affect mood, appetite, and sleep

serotonin

Modulation of ________ action at nerve synapses thought to be target of antidepressants called SSRIs

serotonin

Tryptophan — Bioactive Amine Synthesis

• Reactant: ____________

• Enzyme: ____________ _____________

• Intermediate: ___-_________ ____________

• Enzyme: ___________ ____ _______________

• Cofactor: ______

• Products: ____________, ______

tryptophan, Tryptophan Hydroxylase, 5-hydroxy tryptophan, Aromatic AA Decarboxylase, PLP, serotonin, CO2

What is this a picture of?

tryptophan

What is this a picture of?

serotonin

Glycine — Bioactive Amine Synthesis

• Reactants: ________, _____________

• Enzyme: ______-___________________ _____________

• Cofactor: ______

• Minor products: _____, ______

• Intermediate: 2x _____-__________________

  + 2x H2O

• Intermediate: 4x _________________

• Minor products: 4x ______, ______

• Intermediate: _____________________

• Minor products: 6x _____

  + Fe²⁺

• Final Product: _______

glycine, succinyl-CoA, delta-Aminolevulinate Synthase, PLP, CoA, CO2, delta-Aminolevulinate, Porphobilinogen, NH4-, H2O, Uroporphyrinogen III, CO2, Heme

Where is heme synthesized?

liver, RBCs (erythroid cells)

______ = key component of hemoglobin, myoglobin, and cytochromes

heme

Which bioactive amine is important for transporting oxygen and carbon monoxide?

What amino acid is its precursor?

heme, glycine

What is the amino acid precursor for the bioactive amine heme?

glycine

What is found in feces that gives it its red-brown color?

stercobilin

Degradation of _________ = Bruising process and development 

heme

What is this a picture of?

heme

Degradation of Heme: A Colorful Process

• Reactant: ______ (color = _______)

• Minor products: _____, ____

• Intermediate: ___________ (color = _______)

• Intermediate: ___________ (color = _______)

• Transported to _____ via _______ _______

• Excreted in ______

• Digested via __________ microbes

• Intermediate: ______________

• If reabsorbed: _________ (excreted in ______) (color = ________)

• If NOT reabsorbed: ____________ (color = ________)

heme, purple, Fe2+, CO, Biliverdin, green, Bilirubin, yellow-orange, liver, serum albumin, bile, intestinal, Urobilinogen, Urobilin, yellow, urine, Stercobilin, red-brown

What are the amino acid precursors for the bioactive amine phosphocreatine? (2)

glycine, arginine

Arginine — Bioactive Amine Synthesis (PCr)

• Reactants: _______, __________

• Minor product: ___________

• Intermediate: _________ _________

• Cofactor: _____

• Intermediate: __________

• Travel from _______ to ______ in the circulation

• Enzyme: ________ ________

  + ATP

• Products: ________________, ____

glycine, arginine, ornithine, guanidine acetate, SAM, creatine, kidneys, muscle, Creatine Kinase, phosphocreatine, ADP

Where does creatine synthesis occur?

kidneys

Where does phosphocreatine synthesis occur?

muscle

Acts as energy buffer in muscle 

phosphocreatine

Serum Creatine-Kinase levels = marker for ______ _______

heart attacks

What is this a picture of?

glycine

What is this a picture of?

arginine

What is this a picture of?

creatine

What is this a picture of?

phosphocreatine

What is the amino acid precursor for the bioactive amine nitric oxide?

arginine

Arginine — Bioactive Amine Synthesis (NO)

• Reactants: __________, _______

• Enzyme: ______ ______ _________ (____)

• Products: ______ ______, ___________

arginine, NADPH, Nitric Oxide Synthase, NOS, nitric oxide, citrulline

Which bioactive amine is a free radical gas?

nitric oxide

Which bioactive amine is used for short-distance signaling because it is a hormone that acts locally as it readily diffuses across membranes and breaks down rapidly?

nitric oxide

What are the 3 main functions of nitric oxide?

neurotransmission, blood clotting, vasodilation

Which bioactive amine’s signaling pathway is an important target for pharmaceutical companies?

nitric oxide

Nitric Oxide Signaling Pathway

• In ___________ cells (_____ ______ wall), ___________ binds to Muscarinic GPCR; stimulates ____ production via GALPHA and phospholipase C activity

• IP3 stimulates _____ release from ___ by activating ER membrane channel 

• Ca2+ binds to _________ which activates ______ ______ __________ (_____)

• ______ ______ travels to _______ _______ cell; binds to Guanylate Cyclase; catalyzes production of cGMP from GTP

• cGMP activates _________ ________ ___ (______); induces _____________

endothelial, blood vessel, acetylcholine, IP3, Ca2+, ER, Calmodulin, Nitric Oxide Synthase, NOS, nitric oxide, smooth muscle, Protein Kinase G, PKG, vasodilation

___________ helps in immune response by relaxing blood vessels, allowing white blood cells to get to inflammatory site

vasodilation

Nitric Oxide Signaling Pathway Inhibition

• cGMP ________________ converts cGMP to GMP to turn off signaling pathway, thus _________ blood flow 

• Drugs like ________ (aka ______) block this enzyme to _______ blood flow

Phosphodiesterase, reducing, Sildenafil, Viagra, increase

drugs that provide nitric oxide to relieve Angina Pain (chest pain) by relieving pressure (2)

nitroglycerin, amylnitrate

Heart

• Primary fuels = _____ _____, _______ _______, uses some _______

• Constant __________ (~100,000 beats/day)

• Highly ________; lots of ______________ → need to generate lots of ATP bc it’s constantly moving

• Lack of ___ will cause damage

fatty acids, ketone bodies, glucose, exertion, aerobic, mitochondria, O2

Skeletal Muscle

• Fuel = _______, _____ _____, or ______ _______

  • Fuel used depends on level of ______ and _______

• _______ and ________ respiration

• Doesn’t have FAS or Glucose-6-phosphatase (cannot _____ fatty acids or ______ glucose) 

  • Under normal conditions, muscles use all fuel it _______ to make ____

  • Can’t ______ fuels (except during _________ by breaking down proteins)

• _________ __________ → 1-2% of mass, but much more skeletal muscle so overall this is the major site of _________ storage

• Energy Hierarchy = ____ pool, _________________, ___________ (depleted within 1hr of activity), _____ ______

glucose, fatty acids, ketone bodies, activity, exertion, aerobic, anaerobic, make, export, imports, ATP, export, starvation, glycogen reserves, glycogen, ATP, phosphocreatine, glycogen, fatty acids

During rest/light activity, what are the main fuels used in skeletal muscle to make ATP? (3)

glucose, fatty acids, ketone bodies