Lecture 57

Question 1

nitrogen metabolism

Answer 1

• no storage form of AAs in our body
• nitrogen is most abundant in the atmosphere, but we cannot use this and have to get it from dietary proteins
• dietary proteins break down into AAs which can be used to make body proteins and other N₂-containing compounds (porphyrins (heme), neurotransmitters, hormones, purines, pyrimdines)
• α-amino group is degraded into NH₂ and eventually urea for excretion from the body
• carbon skeleton catabolized substrate OR product of anabolism for various metabolic pathways

pg 1474

Question 2

amino acid pool

Answer 2

Input:

• dietary proteins (~100 g/day) -> needed to maintain amino acid pool
• degradation of body proteins (~400 g/day)
• amino acid synthesis de novo (NEAA)

Output:

• synthesis of body proteins (~400 g/day)
• catabolism to: CO₂ + H₂O + NH₃
• synthesis of other nitrogen containing compounds (~30-40 g/day)

ALL amino acids in body must remain in steady state so the input and output MUST be balanced

pg 1475

Question 3

amino acid pool turnover

Answer 3

• protein turnover is the simultaneous synthesis and degradation of protein molecules
• in healthy, fed adults, the total amount of protein in the body remains constant because the rate of protein synthesis is just sufficient to replace the protein that is degraded

pg 1475

Question 4

amino acid pool: nitrogen balance

Answer 4

• basically: nitrogen_in - nitrogen_out
• 6.25 g protein contain about 1 g nitrogen
• positive N₂ balance: when nitrogen intake exceeds excretion; observed during situations in which tissue growth occurs (childhood, pregnancy, recovery from emaciating illness)
• negative N₂ balance: when nitrogen loss is greater than nitrogen intake; associated with inadequate dietary protein, lack of amino acid, or during physiologic stresses (trauma, burns, illness, surgery)

pg 1476

Question 5

neurotransmitters overview

Answer 5

• split into classical neurotransmitters (acetylcholine, amino acids, amines) and nonclassical neurotransmitters (purines, opioids, tachykinins, nitric oxide)
• focus on small molecule classical neurotransmitters called amines
• amines: catecholamines (dopamine, epinephrine, norepinephrine), serotonin, histamine

pg 1478-1479

Question 6

steps of chemical communication

Answer 6

1. signal production and release (from a neuron)
2. signal reception (signaling molecule to receptor protein)
3. signal transmission and amplification (intracellular signaling proteins)
4. response (target proteins → transport, metabolic, gene regulatory, cytoskeletal, cell cycle, etc)
5. signal termination

pg 1480

Question 7

catecholamines overview

Answer 7

• dopamine, epinephrine, norepinephrine
• synthesis of all catecholamines via a common pathway in the presynaptic neuron
• termination and removal: re-uptake and degradation by 2 enzymes (monoamine oxidase, MAO, and COMT)
• neurons are specialized in producing only 1 type of neurotransmitter
• (nor)epinephrine produced outside CNS (adrenal medulla) and act as hormones

pg 1481

Question 8

catecholamines: synthesis

Answer 8

• precursor: tyrosine
• rate-limiting step: tyrosine hydoxylase (L-tyrosine to L-dopa using O₂ and releasing H₂O)
• coenzymes/cofactors required:
• tetrahydrobiopterin - BH₄ (synthesized from GTP endogenously, inability to produce leads to reduction of catecholamines and serotonin)
• pyridoxal phosphate - PLP (for 2nd step of L-dopa to dopamine)
• ascorbate - vitamin C; copper - Cu²⁺ (both for 3rd step of dopamine to norepinephrine)

norepinephrine converted to epinephrine/adrenaline

pg 1482-1485

Question 9

Parkinson disease

Answer 9

neurodegenerative movement disorder due to insufficient dopamine production as a result of the idiopathic loss of doapmine-producing cells in the brain

pg 1486

Question 10

Parkinson disease treatments

Answer 10

• levodopa (L-dopa) → most common
• carbidopa → inhibits the enzyme converting L-dopa to dopamine in the peripheral nervous system; cannot cross BBB and when used in tandem with L-dopa, it allows more peripheral L-dopa to cross the BBB to reach a more therapeutic level in the CNS

pg 1486

Question 11

catecholamines: termination

Answer 11

• degraded via oxidative deamination using 2 enzymes highly expressed in liver: monoamine oxidase (MAO types A and B) and catechol O-methyltransferase (COMT)

termination mechanisms:

• re-uptake 1 back into the presynaptic neuron (50% to vesicles, 50% destroyed by MAO in terminus)
• re-uptake 2 into the effector cell (degraded by COMT)
• remaining → diffusion into the circulation and destroyed in the liver (BOTH MAO and COMT)
• final metabolites are excreted in the urine

pg 1487

Question 12

MAO inhibitors

Answer 12

• used as antidepressants and treatment of some neurologic disorders
• result in increased levels of NTs in the presynaptic neurons

pg 1487

Question 13

serotonin synthesis

Answer 13

• precursor: tryptophan
• coenzymes required: PLP and BH₄ (same as catecholamines)

pg 1488

Question 14

serotonin termination

Answer 14

• re-uptake into the neuron by SERT (specific transporters)
• degradation by monoamine oxidase (MAO)

pg 1488

Question 15

serotonin implicated in…

Answer 15

• in the CNS: pain, regulation of sleep, appetite, body temp, blood pressure, cognitive functions, and MOOD
• in the periphery: in intestinal mucosal cells → activates neural reflexes associated with intestinal secretion, motility, and sensation
• in the pineal gland: precursor for melatonin

pg 1488

Question 16

selective serotonin uptake inhibitors (SSRI)

Answer 16

result in higher levels of serotonin in the synaptic space

pg 1488

Question 17

histamine synthesis

Answer 17

• precursor: histidine
• coenzyme required: PLP
• histamine does NOT cross the BBB → must be produced in CNS

pg 1489

Question 18

histamine implicated in…

Answer 18

• in the CNS: regulation of food and water intake, thermoregulation and autonomic functions, higher brain functions (learning, memory, circadian rhythms, feeding), immunity
• in the periphery: synthesized in mast cells, allergic and inflammatory mediator

pg 1489

Question 19

nitric oxide (NO) synthesis

Answer 19

• precursor: arginine
• NO is a small, inorganic molecule that acts locally and diffuses easily

Synthesis:

• enzyme: nitric oxide synthase (NOS)
• tissue specific isoforms
• requires NADPH as coenzyme, BH₄

pg 1491

Question 20

NO roles

Answer 20

• smooth muscle: vascular smooth muscle relaxant, produced by eNOS
• platelets: inhibitor of adhesion and aggregation, produced by eNOS
• macrophages: mediator of bactericidial action of free radicals, produced by iNOS
• brain: neurotransmitter in CNS and PNS, produced by nNOS

pg 1492

Question 21

NO in the brain

Answer 21

• precursor: arginine
• synthesis in CNS: when needed (NOT stored in vesicles), diffuses freely (no exocytosis)
• retrograde messenger in the CNS
• inactivation is passive
• uses isoform I (nNOS) → a constitutive isoform with calcium dependence

pg 1493

Question 22

energy production in muscle summary

Answer 22

• conversion between creatine phosphate and ATP is reversible and allows for phosphate molecules to be available
• almost 5x more creatine phosphate present in muscle tissue than ATP

pg 1495

Question 23

phosphocreatine (creatine phosphate)

Answer 23

• high energy phosphate molecule that can reversibly transfer the phospho group to ADP to produce ATP
• serves as reservoir of ~Pi
• “carrier” of high-energy phosphate
• found in brain, skeletal and heart muscle cells
• play important role during exercise
• amount of phosphocreatinine in body is proportional to muscle mass

pg 1496

Question 24

synthesis of creatine phosphate

Answer 24

• begins in the kidney, ends in the liver
• phosphorylation step → in the respective tissue (brain, heart, SKM) by creatine(phospho) kinase (CPK or CK) → reversible step
• if high levels of CPK are in serum, this is a sign of tissue damage
• condensation rxn of Arg + Gly to guanidinoacetate in kidney; methylation of guanidinoacetate to creatine in liver; creatine delivered to tissues to be phosphorylated to creatine phosphate

pg 1497

Question 25

degradation and excretion of creatine phosphate

Answer 25

• spontaneous cyclization to creatinine (non-enzymatic)
• rapidly cleared from the blood and excreted in urine via the kidney → increased blood creatinine levels are used as an indicator of kidney dysfunction
• a typical adult male excretes 1-2 g creatinine daily in the urine and increased levels could be used as diagnostic to measure muscle loss

pg 1498