biochem exam 4/8/24 Flashcards
the more active form of glutamine synthetase is the
- adenylylated form of the enzyme
- de-adenylylated form of the enzyme
- de-adenylylated form of the enzyme
PII is the factor that binds to adenylyl transferase (AT). If PII is uridylylated
- AT preferentially catalyzes the adenylation of glutamine synthetase (GS)
- AT preferentially catalyzes the de-adenylation of GS
- AT preferentially catalyzes the de-adenylation of GS
An elevated glutamine concentration leads to…
A. An increase in the [PII + UMP]
B. A decrease in the [PII + UMP]
C. The de-adenylation of glutamine synthetase
B. A decrease in the [PII + UMP]
When there is a sufficient amount (or more) of gln in a cell, which of the following is true about glutamine synthetase and the associated regulatory enzyme
- AT-PII will be uridylylated, GS will not be adenylylated and GS will be active
- AT-PII will be uridylylated, GS will be adenylylated and GS will be inactive
- AT-PII will not be uridylylated, GS will be adenylylated and GS will be inactive
- AT-PII will not be uridylylated, GS will not be adenylylated and GS will be active
- AT-PII will not be uridylylated, GS will be adenylylated and GS will be inactive
heme is derived from ____ and is broken down to form ____
- arginine, creatine
- glycine, creatine
- glycine, bilirubin
- blirubin, creatine
- glycine, bilirubin
Which of the following statements is incorrect?
A. GABA is derived from glutamate
B. Histamine→histidine
C. Serotonin→tryptophan
D. Dopamine→tryptophan
E. Epinephrine→tyrosine
D. Dopamine→tryptophan
therapies for Parkinson’s disease include
- block formation of L-Dopa
- administer L-dopa to the patient
- accelerate dopamine breakdown
- administer an MAO inhibitor
- administer L-dopa to the patient
- administer an MAO inhibitor
which of the following reactions is part of the normal nucleotide synthesis
- AMP to dAMP
- GDP to dGDP
- TDP to dTDP
- UTP to dUTP
- CMP to CDP
- GDP to dGDP
Folate and/or vitamin B12 is/are required for the synthesis of…
A. dAMP
B. dCMP
C. dGMP
D. dTMP
E. dUMP
D. dTMP
which statement is false
- gout involves uric acid crystals in joints
- purine catabolism leads to uric acid formation
- allopurinol inhibits uric acid breakdown
- allopurinol inhibits xanthine oxidase
- allopurinol inhibits uric acid breakdown
which of the following inhibits the reduction of NDPs to dNDPs
- allopurinol indomethacin
- azaserin, acivicin
- aminopterin, methotrexate
- gemcitabine
- gemcitabine
which of the following are Gln analogs that interfere with nucleotide synthase
- allopurinol indomethacin
- azaserin, acivicin
- aminopterin, methotrexate
- gemcitabine
- azaserin, acivicin
aminopterin, methotrexate, and fluorouracil reduce the synthesis of
- glutamate
- glutamine
- cAMP
- dAMP
- dTMP
- dTMP
Sources of Nitrogen
Ammonia is toxic to mammalian cells and must be immediately used up (assimilated) or converted to urea and removed (Ch 18)
Soluble, biologically useful nitrogen-containing molecules are generally scarce, so organisms are conservative in their use
Ammonia is assimilated into glutamine (major) and glutamate (minor) in mammalian cells.
Glutamine and glutamate are the nitrogen sources for the cellular synthesis of other amino acids and other nitrogenous compounds.
Assimilation of Ammonia into Glutamine (Major Pathway)
Glutamate + glutamine synthetase = acyl-phosphate intermediate
Glutamine is the source of amino groups for most other nitrogenous compounds.
Major Source of Glutamate
Breakdown of excess dietary amino acids by transamination reactions yields high levels of cellular glutamate, shortly after the meal is consumed.
Glutamate is the source of amino groups for most other amino acids.
Assimilation of Ammonia into Glutamate (Minor Pathway)
Km for NH4+ = 1 mM rendering glutamate synthesis only possible when [NH4+] is abnormally high (hyperammonemia).
In cells, both Glutamine and Glutamate are kept at concentrations higher than other amino acids
Allosteric Regulation of Glutamine Synthetase
Each molecule alone partially inhibits the enzyme…
6 of these are derived from glutamine
If all products are present at sufficiently high levels, the enzyme is essentially turned off.
Don’t need it, don’t make it.
Covalent Regulation of Glutamine Synthetase
GS + AMP = OFF
GS = ON
PII + UMP + AT = GS ON (via deadenylation)
PII + AT = GS + AMP = OFF (via adenylation)
Simplified: Covalent Regulation of Glutamine Synthetase
high ATP or high alpha ketoglutarate, low Gln
- AT-PII uridylyated - yes
- GS adenylylated - no
- GS active - yes
low ATP or low alpha-ketoglutarate or high Gln
- AT-PII uridylyated - no
- GS adenylylated - yes
- GS active - no
Essential and Non-Essential Amino Acids
Essential Amino Acids:
- Amino acids that cannot be synthesized (made) by an organism and must be a component of the diet.
Non-Essential Amino Acids:
- Amino acids that can be synthesized by an organism and are not required to be a component of the diet.
Amino Acid Synthesis
Synthesized from 6 common precursors!
- Sometimes more than one way…
We’ve seen some of these already:
Phenylalanine→Tyrosine (PKU) Pyruvate→Alanine (Muscle) Oxaloacetate→Aspartate (Urea Cycle) α-KG → Glutamate (Transamination) Glutamate→Glutamine (Above)
Connections:
Serine→Glycine uses THF (remember?!) Methionine cycle involves SAM, B12, Folate (B9)!
Glycolysis, PPP, CAC, AA Catabolism, etc.
Porphyrins (Heme)
Heme isn’t just for hemoglobin:
Myoglobin, catalase, peroxidase, P450 liver cytochromes
Deficiency in the enzymes in this pathway cause a build-up of toxic porphyrins→ Porphyria
“Mad” King George III
Genetic, can be triggered by meds Different porphyrias, different symptoms Neurological, skin, photosensitivity
heme breakdown
to bilirubin etc.
a stronger antioxidant, but an elevated level in blood may indicate liver disease
heme breakdown color: black/blue/purple
biliverdin breakdown color:
green
bilirubin breakdown in blood:
yellow
creatine from Gly, Arg, Met
a ready source of phosphoryl groups for quick synthesis of ATP (phosphocreatine s later replenished by phosphoryl transfer from ATP)
ADP + PCr = ATP + Cr
delta G = -12.5kJ/mol
Neurotransmitters: Derived from Amino Acids
dopamine, norepinephrine, epinephrine
gamma-aminobutyric acid (butyrate) - GABA
serotonin
histamine
nitric oxide (NO)
From tyrosine:
dopamine, norepinephrine, epinephrine
catecholamines
tyrosine -
deficiency of this coenzyme results in deficiency of catecholamines as well as PKU
dopamine -
too little: associated with Parkinson’s
norepinephrine
regulates blood pressure
epinephrine
fight or flight
Therapy for Parkinson’s Disease
raise dopamine levels (L-dopa)
maintain dopamine levels by inhibiting monoamine oxidase (MAO inhibitors, such as selegiline)
- xadago (safinamide)
L-dopa is the precursor to dopamine
L-dopa crosses the BBB, dopamine cannot
can be metabolized in the periphery
challenge:
must get L-dopa to the brain without being metabolized
if you do not beat this challenge
- side effects
- reduced availability of DOPA in the brain
solution
- co-administer with a DOPA carboxylase inhibitor so that the drug isn’t metabolized to DOPA in the periphery, and therefore more DOPA gets to the brain
from glutamate
GABA
- astrocytes control the biosynthesis and turnover of glutamate and GABA
- there are other ways to treat epilepsy - not just through GABA
- can be co-released with glycine (also inhibitory; AA)
lack associated with epileptic seizures.
treatment: administer GABA analogs or inhibitor breakdown
from tryptophan
serotonin
- suppresses appetite
- induces fatigue
- makes you mellow
brainstem control of respiration
serotonin syndrome: DDI
Trp is also a precursor of melatonin which is involved in the control of circadian rhythms
tetrahydrobiopterin
- deficiency of this coenzyme results in deficiency of serotonin and PKU
Monoamine oxidase
- maintains serotonin levels
from histidine
histamine
released in allergic response and stimulates acid secretion in the stomach
this structural analog interferes with the action of histamines (an H2 receptor antagonist used to treat gastric reflux)
from arginine
nitric oxide
involved in neurotransmission, blood clotting, control of blood pressure
gas
activates GC to cGMP for vasodilation
De Novo (From Scratch) Nucleotide Synthesis
NMPs are synthesized “on phosphorizes” not by adding free bases to ribose
Ribose + P to P-ribose to NMP
not by attaching a pre-formed base to P-Ribose
basically
- start with the P-ribose and synthesize the rest of the P-Ribose
purine nucleotide synthesis
Purine Nucleotide Synthesis: Salvage Pathway
Some tissues can’t De novo, so when RNA/DNA degenerates, bases and nucleosides can be recovered, and recycled back into nucleotides.
adenine + PRPP to adenylyase PPi
enzyme: adenine phosphoribosyltransferase
hypoxanthine + PRPP to inosinate + PPi
guanine + PRPP to guanlyate + PPi
enzyme: hypoxanthine-guanine…
Nucleotide Synthesis
general scheme:
nucleotide synthesis
start mono
add phosphates
Ribose → deoxyribose via reduction
folate, vtamine/coenzyme B12 & DNA synthesis
folate & B12 required for DNA synthesis
B12 and or folate deficiency
one serious consequence of B12 or folate deficiency as N5, N10-Me THF defc. dTMP def. and reduced DNA synthesis
Nucleotide Degradation
purine nucleotides to urc acd to excretion
pyrimidine nucleotides to NH4 to ureaa to excretion
Excessive Purine Catabolism
Following excessive purine consumption or synthesis
If this happens→overproduction of uric acid→ high [uric acid] in the blood and tissues…
Then urate crystals (the salt of uric acid) get deposited in the joints which become inflamed, painful, and arthritic. Additional deposits found in the kidneys
- The above are signs of Gout.
Cause unknown, maybe genetic?
90% of affected individuals are
men > 40 years old
- Effects ~ 1 million Americans
- Joint of big toe affected ~ 50% of cases
Gout
control of Gout:
Limit intake of foods rich in purines: meat (esp: liver), poultry, seafood
Avoid: alcohol, fructose-sweetened drinks, and obesity (these increase risk)
Vitamin C, dairy products, and coffee (not tea) may reduce risk
- Treatment for Gout
Allopurinol – an irreversible inhibitor of xanthine oxidase – the enzyme that converts purines to uric acid
Allopurinol therapy results in the accumulation of xanthine and hypoxanthine (instead of uric acid/urate), which are soluble (uric acid is not)
Other drugs you might see: Probenecid, Febuxostat
Treat pain/inflammation with NSAIDs, steroids, colchicine
Cancer
cancer cells are growing much more rapidly than most normal tissues, and have a great need for nucleotides, precursors of DNA & RNA
a growing array of anti-cancer drugs interfere with nucleotide biosynthesis:
- glutamine analogs - glutamine to source for nucleotides
- inhibition of ribonucleotide reductase - ribose to deoxyribose
- thymidylate synthesis blockers - need T’s
Glutamine Analogs
Looks like glutamine, but isn’t. Interferes with enzymatic reactions involving glutamine and the formation of nucleotides
Gln is a nitrogen donor in many nucleotide synthesis rxns
mechanisms unclear: competitive or suicide inhibition
research only
Ribonucleotide Reductase Inhibition
gemcitabine seems to do that
Blocking dTMP Synthesis
use fluorouracil on dUMP
Resting muscle derives most of its energy from…?
A. Muscle glycogen
B. Fatty acids
C. Blood glucose
D. Phosphocreatine
the cori cycle involves the transport of ____ from muscle tissue to the liver and of _____ from the liver to muscle
- glucose, glutamine
- alanine, glucose
- lactose, glucose
- glucose, lactate
- lactate, glucose
- lactate, glucose
Which of the following carries out only aerobic metabolism and therefore must have access to oxygen (O2)?
A. Liver
B. Adipose tissue
C. Skeletal muscle
D. Cardiac muscle
E. Brain
which of the following normally uses
only glucose as a source of energy
- the liver
- adipose tissue
- skeletal muscle
- cardiac muscle
- the brain
- the brain
which of the following (types of) hormones is relatively fast-acting
- catecholamines
- vitamin D
- Eicosanoids
- retinoids
- steroids
- catecholamines
- Eicosanoids
an elevated level of insulin would lead to a(n) _____ in glucose synthesis in the liver
increase
decrease
decrease
an elevated level of glucagon would lead to a(n) in glycogen breakdown n the liver
increase
decrease
increase
An elevated level of cortisol would lead to a(n) ___ in fatty acid mobilization from adipose tissue.
A. Increase
B. Decrease
A. Increase
an elevated level of epinephrine would lead to a(n) ___ in glucose synthesis in the liver
increase
decrease
increase
an elevated level of epinephrine would lead to a(n) ___ in glucagon secretion
increase
decrease
increase
what effect will an elevated level of insulin have on (i) glycogen breakdown in the liver and muscle and on (ii) fatty acid synthesis in the liver
- (i) promote (ii) promote
- (i) promote (ii) inhibit
- (i) inhibit (ii) promote
- (i) inhibit (ii) inhibit
- (i) inhibit (ii) promote
The TCA cycle is the central metabolic hub
AA carbon skeletons
Electron extractor
Building block and energy import/export
Subcellular locations of the major metabolic pathways
Specialized Functions of Tissues/Organs
liver
- processes fats, carbohydrates, and proteins from det; synthesizes and distributes lipids, ketone bodies, and glucose for other tissues; converts excess nitrogen to urea
brain
- transports ions to maintain membrane potential; integrates inputs from body and surroundings; sends signals to other organs
cardiac muscle
- uses ATP generated aerobically to pump blood
lymphatic system
- carries lipids from the intestine to the liver
adipose tissue
- synthesizes stores and mobilizes triacylglycerols. Brown adipose tissue carriers out thermogenesis
skeletal muscle
- uses ATP generated aerobically or anaerobically to do mechanical work
The Liver
The central metabolic organ; it transforms and exports/imports molecules.
Hepatocytes transform dietary nutrients into fuels and precursors required by other tissues.
Flexible: can adjust enzyme levels to adjust to nutritional state
Oxidative organ: detoxifies foreign organic compounds (Cytochrome P-450 and others)
Regenerates!
carbohydrate metabolism (liver)
fates of glucose 6-phos
1. glucose (blood)
2. glycogen
3. glycolysis to CAC
4. Glyc. to AcCoA to anabolism
5. pentose phosphate pathway
glucose to G-6-P
- free glucose (blood)
- liver glycogen (storage)
- energy via glycolysis and CAC
- acetyl-CoA - synthesis of larger molecules via glycolysis
- NADPH & nucleic acid precursors via the PPP
Amino acid metabolism
fates of AA’s
1. protein (liver)
2. protein (elsewhere)
3. nucleotides etc.
4. deamination
A. urea
B. Pyruvate - glucose, acetyl-CoA
Amino acid users
1. protein synthesis in the liver
2. export to other tissues for protein
3. synthesis of nucleotide, hormones etc
4. deamination for:
a. gluconeogenesis
b. CAC to ATP
c. lipid synthesis
d. transformation into ammonia and urea
fatty acid metabolism
FA’s are the primary fuel in the liver
fates of FA’s
1. liver lipids
2. acetyl-CoA to CAC
a. CAC (energy)
b. ketone bodies
c. cholesterol etc
- plasma lipoproteins
- transport (free FA)
fatty acid uses:
1. storage in lipids (tails)
2. Major oxidative fuel for the liver (beta-oxidation to acetyl CoA to CAC)
3. transformation into ketone bodies, transported to other places
4. formation of cholesterol
5. incorporated into lipoproteins, transported to other places
6. combine with serum albumin, and transport to other places as a source of energy
Adipose Tissue
fatty acids cycle between TAGs and FFAs
2/3 of adipose tissue is TAGs
Skeletal Muscle
The source of energy depends on the activity level
1. At rest: source of energy comes from fatty acids (from adipose tissue) and ketone bodies (from the liver)
- Moderate activity level: source of energy comes from FAs, KBs, AND glucose
- Heavy activity level: source of energy comes from all of the above AND muscle glycogen (transformed into lactate) AND phosphocreatine
Time course of fuel consumption
creatine phosphate
anaerobic metabolism
ATP
the Cori cycle
how muscles use and replenish glycogen with the assistance of the liver
muscle: during heavy exercise, glycogen is broken down and anaerobic glycolysis leads to the formation of ATP and lactate
liver: rapid respiration produces ATP, which is used to form glucose from lactate in the liver
Heart Muscle and Brain
heart muscle
- completely aerobic
- mitochondria abundant (~50% of cell volume)
- fuel: FA’s (main source), glucose, KB’s phosphocreatine (minor source)
- lack of O2 fatal
brain
- normally uses only glucose, but can use KB’s
- very active: accounts for 20% of O2 use when the body is at rest
types and classes of hormones
autocrine: acts on the same cells
paracrine: acts on adjacent cells
endocrine: acts on distant cells
- Biosynthesis
- Storage and Secretion
- Transport
- Binding
- Relay and Amplification (cellular response)
- Breakdown
Hormones
cell surface receptor
- peptide or amine hormone binds to a receptor on the outside of the cell; acts through the receptor without entering the cell
nuclease receptor
- steroid or thyroid hormone enters the cell; hormone-receptor complex acts in the nucleus
Hormones
plasma membrane receptors; relatively fast-acting
Peptide Hormones
3-200+ amino acids in length
Pancreatic: insulin, glucagon, somatostatin – growth hormone inhibiting hormone – GHIH)
Thyroid: calcitonin (calcium homeostasis and metabolism)
All hypothalamic and pituitary hormones
Catecholamine Hormones
Tyrosine (precursor)
→ L-DOPA
→ Dopamine
→ Norepinephrine
→ Epinephrine (Chapter 22)
Eicosanoid Hormones
Hormones
steroid hormones:
cholesterol to progesterone to cortisol or aldosterone or testosterone
Vitamin D
calcium homeostasis and metabolism to
7-dehydrocholesterol + UV light to vitamin D3 to 25-hydroxycholecaliiferol to 1,25-dihydroxycholecalciferol
Retinoid Hormones
Embryonic Development, Vision
beta carotene to vitamin A1 (retinol) to retinoic acid
Hormones
hormone regulation of fuel metabolism
peptides
- insulin (high blood glucose)
- glucagon (low blood glucose)
catecholamine
- epinephrine (stress; fast acting)
steroid
- cortisol (stress; slow acting)
thyroid hormones that regulate metabolism
Insulin
metabolic effect