Pulm/Renal - Biochemistry - Phospholipids, Sphingolipids, Eicosanoids; the Urea Cycle: Hyperammonemias; Nucleotide Metabolism Flashcards
Name three subtypes of phospholipid.
Phosphoglycerides
Plasmalogens
Sphingolipids
Describe the differences in chemical structure between the following phospholipids:
Phosphoglycerides
Plasmalogens
Sphingolipids
Phosphoglycerides - polar head + 2 esterified fatty acids
Plasmalogens - polar head + 1 esterified fatty acid + 1 etherified fatty acid
Sphingolipids - polar head + 1 ceramide (amide-bonded fatty acid) + 1 sphingosine (enol attachment)
What are the two main types of sphingolipid?
- Sphingomyelin
- Glycolipids (e.g. glucocerebroside, gangliosides, etc.)
Sphingomyelin is basically a phospholipid (specifically, a sphingolipid) with what polar head?
Phosphocholine
What are the basic steps of phosphoglyceride synthesis?
DHAP or glycerol –>
glyceral 3-phosphate –>
activated fatty acic groups added to C1 and C2 –>
head group attached to 3-phosphate
What are the three tissues that are major producers of phosphoglycerides?
Liver
Intestinal epithelium
Lungs (for surfactant)
What are the two major components of pulmonary surfactant?
Surfactant is __% lipid and __% protein.
Dipalmitoylphosphatidylcholine (DPPC),
phosphatidylglycerol;
90, 10
You need to determine fetal surfactant production. Where do you get a sample?
A lecithin:sphingomyelin reading of 1.2 indicates what?
(Note: lecithin is an old term for phosphatidylcholine)
The amniotic fluid;
immature production (<2.0)
What substance should be given to mothers going into preterm labor to reduce their child’s risk of respiratory distress syndrome?
Glucocorticoids
What effect does surfactant have on the alveolus?
Decreased surface tension / elastance;
increased compliance
What is a normal lecithin:sphingomyelin reading for mature lungs?
(Note: lecithin is an old term for phosphatidylcholine)
2:0 - 2:5
Lecithin:sphingomyelin levels are useful in measuring lung maturity.
Lecithin is another name for what substance?
Phosphatidylcholine
Besides their structural role in membranes, what role do plasmalogens (a type of phospholipid) have in cellular protection?
They act as ‘scavengers’ for free radicals, sparing nearby fatty acids and other structures
The nomenclature of plasmalogens is similar to phosphoglycerides.
Describe any differences, using phosphatidylcholine as an example phosphoglyceride.
Phosphoglyceride: Phosphatidylcholine
Plasmalogen: Phosphatidalcholine
Where does plasmalogen (a type of phospholipid) synthesis occur?
What disorder results when peroxisome biogenesis is inhibited?
Peroxisomes;
Zellweger syndrome (death usually occurs within 6 mo. - 1 year following birth)
What enzyme cleaves the C-1 esterified fatty acid from a phosphoglyceride?
What enzyme cleaves the C-2 esterified fatty acid from a phosphoglyceride?
What enzyme cleaves the C-3 phosphate group from a phosphoglyceride?
Phospholipase A1;
phospholipase A2;
phospholipase C
What enzyme cleaves the C-1 esterified fatty acid from a phosphoglyceride?
Phospholipase A1
What enzyme cleaves the C-2 esterified fatty acid from a phosphoglyceride?
Phospholipase A2
What enzyme cleaves the C-3 phosphate group from a phosphoglyceride?
Phospholipase C
Name the function of each of the following:
Phospholipase A1
Phospholipase A2
Phospholipase C
Cleave the phosphoglyceride C-1 fatty acid from the glycerol back bone
Cleave the phosphoglyceride C-2 fatty acid from the glycerol back bone
Cleave the phosphoglyceride C-3 phosphate group from the glycerol backbone
All sphingolipid synthesis start with a simple ___________.
To create sphingomyelin, add ___________.
To create glucosylcerebroside , add ___________.
To create galactosylcerebroside , add ___________.
Ceramide;
phosphocholine,
glucose,
galactose
Sulfatides are a type of sphingolipid made by the ____________ of galactosylcerebrosides in the CNS oligodendrocytes.
If multiple sugars are added to a ceramide, a ______________ results. Adding ________ acid to this results in a ganglioside.
Sulfation;
globoside,
sialic (N-acetylneuraminic)
Type A Niemann-Pick disease results from dysfunction in the metabolism of what substance?
Type B Niemann-Pick disease results from dysfunction in the metabolism of what substance?
Type C1 Niemann-Pick disease results from dysfunction in the metabolism of what substance?
Type C2 Niemann-Pick disease results from dysfunction in the metabolism of what substance?
Sphingomyelin;
sphingomyelin;
cholesterol;
cholesterol
How does type A Niemann-Pick disease manifest?
How does type B Niemann-Pick disease manifest?
More severe form: sphingomyelin accumulation in liver, CNS, and spleen
–> neurodegeneration/intellectual disability and early death;
less severe form: no significant neurological involvement
–> patients typically survive into adulthood
What two enzymes are responsible for sphingomyelin degradation?
Which is deficient in type A Niemann-Pick disease?
Which is partially inactivated in type B Niemann-Pick disease?
Sphingomyelinase, ceramidase;
sphingomyelinase;
sphingomyelinase
What two enzymes are responsible for sphingomyelin degradation?
A deficiency of which enzyme is responsible for Farber disease? What accumulates in this disorder?
Sphingomyelinase, ceramidase;
ceramidase, ceramides
Metachromatic leukodystrophy results from a deficiency of what enzyme?
Resulting in a buildup of what substance?
Arylsulfatase;
sulfatides
Virtually each sphingolipidosis is due to a defect in metabolic pathways breaking down substrate to what eventual product?
Ceramide
What are the three main eicosanoids?
What are eicosanoids?
Prostaglandins, thromboxanes, leukotrienes;
potent cellular regulators: short-lived, local/paracrine signalling molecules
What are some of the functions of eicosanoids?
Pain, swelling, fever (prostaglandins)
Blood coagulation (thromboxanes)
Inflammatory response (leukotrienes)
Eicosanoids are derived from what precursor?
How does this precursor become available?
Arachidonic acid (an ω-6 fatty acid);
(1) phospholipase A2 cleaves it from the C-2 of membrane phospholipids,
(2) it is synthesized from linoleate
How do glucocorticoids decrease the availability of arachidonic acid to a cell?
What immediate effect does this have?
They inhibit phospholipase A2;
decreased eicosanoid (prostaglandins, leukotrienes, thromboxanes) production
What substance inactivates phospholipase A2, thus decreasing the amount of arachidonic acid available to a cell?
Glucocorticoids
After arachidonic acid is cleaved from C-__ of a membrane phospholipid, what are the enzymes that process it into its eicosanoid (prostaglandins, thromboxanes, leukotrienes) products?
2;
cyclooxygenase-1, cyclooxygenase-2, lipooxygenase
Cyclooxygenases turn arachidonic acid into what initial product? (With what intermediate?)
This product is a precursor to what?
Prostaglandin H2 (PGH2) (with PGG2 as an intermediate);
all other prostaglandins, all thromboxanes
Cyclooxygenases produce what from arachidonic acid?
Lipooxygenases produce what from arachidonic acid?
Prostaglandins, thromboxanes;
leukotrienes
What effect do aspirin and other NSAIDs have on eicosanoid production?
NSAIDs block cyclooxygenase and inhibit its expression,
thus decreasing prostaglandin and thromboxane production
Which NSAID irreversibly acetylates the COX enzymes?
Aspirin
Via what chemical reaction do acetominophen and NSAIDs block the COX enzymes?
Identify any of the following that irreversibly inhibit the COX enzymes:
Acetominophen
Ibuprofen
Ketorolac
Aspirin
Naproxen
Acetylation;
aspirin
What side effects does regular aspirin use have?
Abdominal discomfort, ulcer formation, extended bleeding time
What is the major ingredient in Nuprin?
What is the major ingredient in Motrin?
What is the major ingredient in Advil?
Ibuprofen
Ibuprofen
Ibuprofen
Which is more powerful and longer lasting, ibuprofen or acetominophen?
Ibuprofen
What is a common side effect of ibuprofen use?
What is a potential side effect of frequent acetominophen use?
Stomach irritation;
liver toxicity
True/False.
All of the following are NSAIDs and have anti-inflammatory, anti-pyretic, and analgesic properties.
Acetominophen
Ibuprofen
Ketorolac
Aspirin
Naproxen
False.
Acetominophen is not an NSAID and has no anti-inflammatory properties
What is a dangerous side effect of the medication celecoxib (Celebrex) (a selective COX-2 inhibitor)?
Increased risk of stroke and heart attack
Which COX enzyme is constitutively expressed in nearly all tissues and has normal, physiological functions?
Describe the other COX enzyme.
COX-1;
the COX-2 enzyme is induced by cytokines/growth factors (from activated immune and inflammatory cells), and has activity due to more abnormal, pathologic functions
Which is more responsible for the pain, swelling, redness, and heat associated with inflammatory responses, COX-1 or COX-2?
COX-2
(COX-1 = more physiologic functions;
COX-2 = more pathologic functions)
Which NSAID has antiplatelet activities?
How?
Aspirin;
by irreversibly inhibiting the COX enzymes and decreasing thromboxane A2 synthesis
(the other NSAIDs are reversible)
What is the main thromboxane?
What functions does it have?
Thromboxane A2;
platelet aggregation, vasoconstriction
Which COX enzyme product helps to oppose the platelet aggregation and vasoconstriction induced by thromboxane A2?
Prostaglandin I2 (PGI2) (prostacyclin)
What are the main functions of leukotrienes?
Mediating: (1) the allergic response, (2) vasoconstriction, (3) bronchoconstriction, and (4) chemotaxis
Via what mechanism can aspirin and some NSAIDs cause an overproduction of leukotrienes?
By blocking PG and thromboxane production, the remaining arachidonic acid is shunted to become leukotrienes
In what form are carbohydrates stored in the body?
In what form are lipids stored in the body?
In what form are proteins stored in the body?
Glycogen;
triglycerides;
proteins are not stored in the body (excess protein is rapidly excreted)
What are the three basic steps of amino acid catabolism?
1. A transamination reaction removes the amino group as ammonia (leaving behind a keto acid skeleton)
2. The urea cycle converts the ammonia to urea
3. The ketoacid skeleton is oxidized and converted to useful metabolites (e.g. for anapleurotic reactions)
How does a typical transamination reaction work?
An amino acid and a ketoacid swap an amino group
(converting the ketoacid to an amino acid and the amino acid to a ketoacid)
What cofactor is needed for all transamination reactions?
Pyridoxal phosphate (from pyridoxine, vitamin B6)
What happens to the ammonium (NH4+) that is produced in the first steps of amino acid degradation (when the amino group is removed via transamination reactions)?
It is either:
(1) used in the synthesis of amino acids, biological amines, or nucleotides
or
(2) turned into carbamoyl phosphate to enter the urea cycle
The initital steps of degradation of any amino acid typically involve transamination of the amino acid’s amino group to what molecule?
What is formed?
α-Ketoglutarate;
glutamate
(and the amino acid being degraded is converted to its ketoacid equivalent)
What is glutamate’s corresponding ketoacid (following deamination)?
What is alanine’s corresponding ketoacid (following deamination)?
α-Ketoglutarate;
pyruvate
What is pyruvate’s (a ketoacid) corresponding amino acid (following amination)?
What is α-ketoglutarate’s (a ketoacid) corresponding amino acid (following amination)?
Alanine;
glutamate
True/False.
All transamination reactions are irreversible and require pyridoxal phosphate as a cofactor.
False.
All transamination reactions are readily reversible and require pyridoxal phosphate as a cofactor.
Most amino acid degradation in the muscle results in what amine carrier(s) that take(s) NH4+ to the liver (and to a lesser extent, the kidneys) for entry into the urea cycle?
Most amino acid degradation in non-muscle extrahepatic cells results in what amine carrier(s) that take(s) NH4+ to the liver (and to a lesser extent, the kidneys) for entry into the urea cycle?
Alanine and glutamine;
glutamine
Via what type of reactions does a glutamine entering the liver lose both its R-group amine (NH4+) (and becomes glutamic acid) and then its amino group (NH4+) (becoming α-ketoglutarate)?
Via a series of transamination and non-transamination reactions
(the NH4+ then enters the urea cycle)
Describe the steps of the Cahill (glucose-alanine) cycle.
Muscle proteins that are broken down have their NH4+ groups transferred to α-ketoglutarate, forming glutamate, and then to pyruvate, forming alanine.
The alanine travels in the blood to the liver. Alanine transaminase (ALT) in the liver turns the alanine back into pyruvate.
The pyruvate is used in gluconeogenesis and glucose is formed.
Describe the steps of the Cahill (glucose-alanine) cycle in very simplified terms.
Muscle protein –> alanine (via muscle alanine transaminase (ALT)) –> into the bloodstream
Alanine –> pyruvate (via liver alanine transaminase (ALT)) –> glucose –> into the bloodstream
The Cahill cycle uses muscle ___________ to create ____________ in the liver.
The Cori cycle uses muscle ___________ to create ____________ in the liver.
Alanine, glucose;
lactate, glucose
What is the purpose of alanine transaminase (ALT) in the muscle?
What is the purpose of alanine transaminase (ALT) in the liver?
To convert glutamate (from broken down amino acids’ NH4+ + α-ketoglutarate) to pyruvate, forming alanine.
To convert alanine (the above step) to pyruvate, allowing it to enter gluconeogenesis.
In what organs does the urea cycle take place?
Does it take place in the cytosol or mitochondria or another organelle or some combination?
The liver
(and to a lesser extent, the kidneys);
it starts in the mitochondria and ends in the cytosol
What are the major inputs for the urea cycle?
What are the major products of the urea cycle?
Glutamine, alanine, glutamate;
fumarate, urea, orthinine
(with orthinine going back into the cycle)
The formation of what two urea cycle intermediates occurs in the mitochondria?
Does the majority of the cycle occur in the mitochondria or the cytosol?
Carbamoyl phosphate, citrulline;
the cytosol
Which is involved in the Cahill cycle, liver alanine aminotransferase (ALT) or liver aspartate aminotransferase (AST)?
Which is involved in the urea cycle, liver alanine aminotransferase (ALT) or liver aspartate aminotransferase (AST)?
ALT;
AST
What is the ketoacid equivalent of the amino acid alanine?
What is the ketoacid equivalent of the amino acid glutamate?
What is the ketoacid equivalent of the amino acid aspartate?
Pyruvate (interconverted via ALT);
α-ketoglutarate;
oxaloacetate (interconverted via AST)
What is the amino acid equivalent of the ketoacid α-ketoglutarate?
What is the amino acid equivalent of the ketoacid oxaloacetate?
What is the amino acid equivalent of the ketoacid pyruvate?
Glutamate;
aspartate (interconverted via AST);
alanine (interconverted via ALT)
What two molecules (an amino acid and a ketoacid) are interconverted via liver alanine aminotransferase (ALT)?
What two molecules (an amino acid and a ketoacid) are interconverted via liver aspartate aminotransferase (AST)?
Alanine / pyruvate;
aspartate / oxaloacetate
What two transaminases are often assessed as part of a liver function panel (bloodwork)?
Alanine aminotransferase (ALT);
aspartate aminotransferase (AST)
What do elevated levels of ALT and AST indicate?
Liver damage
What is the main purpose of the urea cycle?
To eliminate toxic ammonia from the body in the form of urea
The glutamate, alanine, and glutamine that function as NH4+ carriers to the liver are all converted to what singular NH4+ carrier before entering the mitochondria to contribute to the urea cycle?
Glutamate
What activated carrier takes an NH4+ group from glutamate once glutamate enters the liver mitochondria?
What enzyme catalyzes the reaction?
Carbamoyl phosphate;
carbamoyl phosphate synthetase I
(rate-limiting step of the urea cycle)
How is carbamoyl phosphate formed?
CO2 (from bicarbonate)
+
NH4+ (from glutamate)
+
hydrolysis of 2 ATP
Carbamoyl phosphate is the input substrate for what cycle?
What enzyme catalyzes its synthesis?
The urea cycle;
carbamoyl phosphate synthetase I
List the general reactions of the urea cycle.
- Orthinine + carbamoyl phosphate –> citrulline
- Citrulline + ATP + aspartate –> arginosuccinate
- Arginosuccinate –> Arginine + fumarate
- Arginine + H2O –> Orthinine + urea
What is the first step of the urea cycle?
What enzyme catalyzes this step?
Carbamoyl phosphate combines with orthinine to form citrulline;
orthinine transcarbamolyase
What is the first reaction of the urea cycle (analogous to oxaloacetate and acetyl-CoA coming together to make citrate)?
Orthinine (regenerated cyclically like oxaloacetate) and carbamoyl phosphate (an activated carrier analogous to acetyl-CoA) come together to make –>
citrulline (analogous to citrate in this example)
What reaction is catalyzed by orthinine transcarbamoylase?
Where does this reaction take place?
The first step of the urea cycle
(orthinine + carbamoyl phosphate –> citrulline);
the mitochondrial matrix
What is the second step of the urea cycle?
What enzyme catalyzes the reaction?
Citrulline + ATP –> arginosuccinate;
arginosuccinate synthetase
What is the third step of the urea cycle?
What enzyme catalyzes the reaction?
Arginosuccinate –> fumarate (enters CAC) + arginine;
arginosuccinatase
What is the fourth step of the urea cycle?
What enzyme catalyzes the reaction?
Arginine –> urea + orthinine;
arginase
Which steps of the urea cycle take place in the cytosol?
Which steps of the urea cycle involve ATP input?
Which intermediates of the urea cycle enter or exit the mitochondria?
2, 3, and 4;
1 (2 ATP) and 2 (1 ATP);
orthinine enters, citrulline exits
What are the four enzymes of the urea cycle?
What preparatory enzyme catalyzes the rate-limiting step?
1. Orthinine transcarbamoylase
2. Argininosuccitate synthetase
3. Argininosuccinatase
4. Arginase
Carbamoyl phosphate synthetase I
Describe the allosteric regulation of the urea cycle.
Aspartate –> stimulates N-acetylglutamate synthestase (which combines acetyl-CoA and glutamate) –> N-acetylglutamate activates carbamoyl phosphate synthetase I
What effect do elevated levels of ammonia (NH3) have on the body?
Depleted citric acid intermediates –>
CNS ATP depletion –>
neurological symptoms
What are some common signs / symptoms typical of deficiencies involving enzymes of the urea cycle?
Hyperammonemia, seizures, coma, early death
What are some potential signs/symptoms associated with a deficiency of carbamoyl phosphate synthetase I?
Hyperammonemia, seizures, coma, early death
What are some potential signs/symptoms associated with a deficiency of orthinine transcarbamoylase?
(Think in terms of S/Sy and changes in metabolite levels.)
Hyperammonemia, seizures, coma, early death;
orotic acidemia, decreased citrulline and arginine
What are some potential signs/symptoms associated with a deficiency of argininosuccinate synthetase?
(Think in terms of S/Sy and changes in metabolite levels.)
Hyperammonemia, seizures, coma, early death;
citrullinemia
What are some potential signs/symptoms associated with a deficiency of argininosuccinitase?
(Think in terms of S/Sy and changes in metabolite levels.)
Hyperammonemia, seizures, coma, early death;
argininosuccinic acidemia
What are some potential signs/symptoms associated with a deficiency of arginase?
(Think in terms of S/Sy and changes in metabolite levels.)
Hyperammonemia, seizures, coma, early death;
arginemia, slowed growth, intellectual disability
What are some potential signs/symptoms associated with a deficiency of N-acetylglutamate synthetase (a potent stimulator of carbamoyl phosphate synthetase I)?
(Think in terms of S/Sy and changes in metabolite levels.)
Hyperammonemia, seizures, coma, early death;
developmental delay, intellectual disability
What are some examples of deficiencies involving enzymes of the urea cycle that can cause hyperammonemia (and potential seizures, coma, early death)?
Carbamoyl phosphate synthetase I;
N-acetylglutamate synthetase;
orthinine transcarbamoylase;
argininosuccinate synthetase;
argininosuccinitase;
arginase
Other than serum ammonia, what will be elevated in patients with an argininosuccinate synthetase deficiency?
Other than serum ammonia, what will be elevated in patients with an orthinine transcarbamoylase deficiency?
Citrulline;
orotic acid
Other than serum ammonia, what will be elevated in patients with an an arginase deficiency?
Other than serum ammonia, what will be elevated in patients with an an argininosuccinitase deficiency?
Arginine (argininemia);
argininosuccinic acid
What are three medications used in treating hyperammonemia?
Lactulose;
benzoate;
phenylbutyrate
What is the main organ system affected by hyperammonemia?
What is the main organ system (if dysfunctional) that is likely causing hyperammonemia?
The CNS;
the liver
What are the following three medications used to treat?
Lactulose
Benzoate
Phenylbutyrate
What are their respective mechanisms of action?
Hyperammonemia;
Lactulose - intestinal flora break it down into lactate and acetate –> acidifies gut –> NH3 becomes NH4+ –> NH4+ is less readily absorbed –> serum ammonia levels decrease
Benzoate* - decreases serum glycine
Phenylbutyrate* - decreases serum glutamine
(*decreases the level of free amino acids –> decreases the body nitrogen load)
Name several examples of nucleotides.
(Don’t make a comprehensive list. Just recognize the various types of nucleotide.)
Genetic material monomers (dATP, dGTP, dUTP, dTTP, dCTP)
ATP, cAMP, GTP (energy carriers) UDP
NAD+, FAD, CoA, SAM (cofactors)
Where does most de novo purine and pyrimidine synthesis occur (organ system)?
The liver
What is a common precursor and intermediate to de novo purine and pyrimidine synthesis?
PRPP
(phosphoribosyl pyrophosphate - basically, activated ribose)
True/False.
Both purine and pyrimidine de novo synthesis involve multienzyme complexes, and both purine and pyrimidine de novo synthesis begin with their bases already attached to phosphoribosyl pyrophosphate.
False.
Both purine and pyrimidine de novo synthesis involve multienzyme complexes. (This part is true.)
Purine de novo synthesis begins with the purine bases already attached to PRPP; pyrimidine bases are synthesized and then attached to PRPP.
What sugar is used for both pyrimidine and purine de novo synthesis?
How is it deoxygenated to form deoxyribose?
Ribose;
via ribonucleotide reductase
The synthesis of 5-phosphoribosyl 1-pyrophosphate for purine and pyrimidine de novo synthesis is inhibited by what?
It is activated by what?
Inactivated by: purine nucleotides
Activated by: inorganic phosphate
What precursor must be synthesized before purine de novo synthesis can occur?
Purine synthesis occurs in what multienzyme complex?
Phosphoribosyl pyrophosphate;
the purinosome
What is the first step of purine de novo synthesis?
What enzyme catalyzes the reaction?
An NH3 group is transferred from glutamine to PRPP;
glutamine phosphoribosyl pyrosphosphate amidotransferase
Describe the feedback activation and inhibtion for the first step of purine de novo synthesis (NH3 group transferred from glutamine to PRPP by glutamine phosphoribosyl pyrophosphate amidotransferase).
Activation: PRPP
Inhibition: IMP, AMP, GMP
How many steps are involved in the de novo synthesis of a purine nucleotide?
How many ATP are used?
10;
6 (steps 2, 4, 5, 6, and 7)
What is inosine?
What is guanosine?
What is adenosine?
Hypoxanthine + ribose
Guanine + ribose
Adenine + ribose
Which steps of purine synthesis require tetrahydrofolate?
What category of drugs can block these reactions?
Steps 3 and 9;
folic acid analogs (e.g. methotrexate)
Describe the function of each of these drug categories:
Sulfonamides
Folic acid analogs (e.g. methotrexate)
Sulfonamides - block bacterial production of tetrahydrofolate
Folic acid analogs (e.g. methotrexate) - block purine de novo synthesis in human cells
What is the final product of purine de novo synthesis?
What is its base?
What happens next?
Inosine 5’-monophosphate (IMP);
hypoxanthine;
either adenosine MP or guanosine MP is formed from this final product
Describe the formation of adenosine MP from inosine MP (e.g. enzymes involved, regulation, etc.).
Describe the formation of guanosine MP from inosine MP (e.g. enzymes involved, regulation, etc.).
What is the function and mechanism of mycophenolic acid?
Mycophenolic acid is an immunosuppressant that blocks IMP dehydrogenase in proliferating T and B cells (blocking de novo synthesis of guanine nucleotides)
Describe the breakdown of a purine.
(1) A 5’ nucleotidase removes the phosphate groups
(2) A purine nucleoside phosphorylase removes the ribose, leaving a free base behind
Breakdown of adenine and guanine converge on what base?
What occurs next?
Hypoxanthine (as part of inosine);
xanthine oxidase oxidizes the hypoxanthine into xanthine, then into uric acid (which is readily excreted)
The uric acid seen in gout is an end product of what process?
Purine degradation
Describe the crystals found in gout.
Name a few medications used to treat gout.
Needle-shaped urate crystals;
colchicine, indomethacin, prednisone, probenecid, allopurinol
In what human tissue does adenosine deaminase (turns adenosine to inosine) have the highest level of activity?
So, what does an adenosine deaminase deficiency cause?
Lymphocytes;
buildup of dATP –> ribonucleotide reductase inhibition –> lymphocyte death –> SCID
What disorder can be caused by an adenosine deaminase deficiency or a purine nucleoside phosphoylase deficiency, among other causes?
SCID
True/False.
Not all purines resulting from normal turnover of cellular nucleic acids will be degraded and excreted.
True.
The purine salvage pathway can reuse many purines
What are the two enzymes of the purine salvage pathway?
Is this process reversible or irreversible?
Adenine phosphoribosyltransferase (APRT),
hypoxanthine-guanine phosphoribosyltransferase (HGPRT);
irreversible
What is Lesch-Nyhan syndrome?
What are some of its signs/symptoms?
How is it treated?
A defiency of hypoxanthine-guanine phosphoribosyl transferase;
gout, self-mutilation, cognitive deficits, motor dysfunction;
allopurinol (just for the hyperuricemia)
Why does a deficiency of hypoxanthine-guanine phosphoribosyl transferase result in hyperuricemia?
What is this condition called?
It is a defect in the purine salvage pathway;
Lesch-Nyhan syndrome
True/False.
The pyrimidine ring is synthesized/constructed on a preexisting ribose monomer.
False.
The purine ring is synthesized/constructed on a preexisting ribose monomer.
(The pyrimidine ring is synthesized before being attached to the ribose monomer.)
In what way are the urea cycle and pyrimidine de novo synthesis similar?
How is the above part of the process different between the two?
Both begin with the formation of carbamoyl phosphate from CO2 and NH3 (the amino group comes from glutamate);
the urea cycle uses carbamoyl phosphate synthestase I (a mitochondrial CPS) while pyrimidine synthesis uses carbamoyl phosphate synthestase II (a cytosolic CPS)
What enzyme is part of the rate-determining step for pyrimidine de novo synthesis?
What enzyme is part of the rate-determining step for purine de novo synthesis?
What enzyme is part of the rate-determining step for the urea cycle?
Carbamoyl phosphate synthestase II
Glutamine phosphoribosyl pyrophosphate amidotransferase
Carbamoyl phosphate synthetase I
How is carbamoyl phosphate synthetase II activated?
How is it inhibited?
ATP, PRPP;
UTP (the end product of pyrimidine synthesis)
Why can orotic aciduria often be treated with uridine?
The uridine is converted to UMP (the final product of pyrimidine de novo synthesis and allosteric inhibitor)
The blocking of what enzyme(s) in pyridmidine de novo synthesis can result in orotic aciduria?
How is this condition treated?
Orotate phosphoribosyl transferase,
OMP decarboxylase (Note: both are sections of the bifunctional enzyme UMP synthase);
uridine administration (the final product and allosteric inhibitor of pyrimidine de novo synthesis)
Why is orotic acid elevated in cases of orthinine transcarbamolyase deficiency (an enzyme of the urea cycle, seemingly unrelated to orotic acid)?
Carbamoyl phosphate builds up, stimulating de novo synthesis of pyrimidines
A deficiency of either of the last two enzymes of pyridmidine de novo synthesis (orotate phosphoribosyl transferase and OMP decarboxylase) can result in orotic aciduria.
These enzymes are both parts of what bifunctional enzyme unit?
UMP synthase
What is the main activator for carbamoyl phosphate synthetase I (of the urea cycle)?
What is the main activator for carbamoyl phosphate synthetase II (of pyrimidine de novo synthesis)?
N-acetylglutamate
Phosphoribosyl pyrophosphate
What substrate must be present before each of the following can occur (a different substrate specific to each one)?
The urea cycle
Purine de novo synthesis
Pyrimidine de novo synthesis
Carbamoyl phosphate
PRPP
Carbamoyl phosphate and PRPP
What enzyme acts on diphosphate nucleotides (e.g. ADP, GDP) and turns them into their 2’ deoxygenated versions?
What substrate reduces the enzyme between each nucleotide that is reduced?
Ribonucleotide reductase
thioredoxin reductase (to reduce the now-oxidized enzyme)
What is the potent allosteric activator of ribonucleotide reductase?
What is the potent allosteric inhibitor of ribonucleotide reductase?
What is a medication targeting ribonucleotide reductase?
ATP;
dADP;
hydroxyurea
What enzyme does hydroxyurea block?
Has this specific function been linked to its effects in sickle cell anemia?
Ribonucleotide reductase;
no
Which deoxynucleotide is not formed by ribonucleotide reductase from its diposphate nucleotide (e.g. ADP to dADP)?
Thymidine
How can cytosine be turned into uracil?
How can uracil be turned into thymidine?
Deamination;
methylation (via thymidylate synthase)
Describe the final step of thymidine (dTMP) synthesis.
Thymidylate synthase methylates dUMP using N5,N10 -methylene-tetrahydrofolate as a cofactor
Thymidylate synthase requires what cofactor?
What enzyme regenerates this cofactor?
N5,N10-methylene-tetrahydrofolate;
dihydrofolate reductase (and serine hydroxymethyl transferase)
Which medication blocks dihydrofolate reductase? This indirectly inhibits the action of what other enzyme?
Which medication blocks bacterial dihydrofolate reductase?
Methotrexate (a folate analog), thymidylate synthase;
trimethoprim
Name the respective enzyme(s) inhibited by each of the following:
Hydroxyurea
Methotrexate
Trimethoprim
Ribonucleotide reductase
Dihydrofolate reductase (and thus, thymidylate synthase)
Bacterial dihydrofolate reductase
True/False.
Large, long-term folate stores are kept in the liver.
False.
Folate is not stored in any significant quantity and must be replaced fairly consistently.
