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191 Cards in this Set

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  • Back
When is the peroxisomal β oxidation cycle used?
When very long fatty acid chains are present b/c they cannot enter the mitochondrial matrix for β oxidation when they are long
How does peroxisomal β oxidation differ from mitochondrial? What is the 1st oxidation dependent on?
1. peroxisomal doesn't provide as much ATP because it generates H202 by using FADH.
2. first oxidation is catalyzed by and FAD dependent acyl CoA oxidase?
Where is NADH reoxidation done in peroxisomal β oxidation?
Outside the peroxisome, not directly by the mitochondrial ETC
What syndrome resluts because of peroxisomes are absent? What accumulates?
Zellweger syndrome--accumulation of VLFA
What results from a defect in perosisomal oxidation of VLFA's at neonatal onset? What accumulates?
X-linked adrenoleukodystrophy resulting in accumulation of VLFA's
Are both FADH and NADH formed in both mitochondrial and peroxisomal β oxidation cycles?
Yes, but peroxisomal isn't as efficient at ATP production b/c FADH is used to form H202
Why does α oxidation occur?
Alkyl branches at odd # C's block the beta C making it unavailable for beta oxidation.
What happens in α oxidation?
beta C is UNblocked by αhydroxylase and α oxidase==
1. branched chain FA
2. convert odd # to even #FA
& visa vera
3. α hydroxy acids can form
How does the C frameshift of α oxidation work?
Move one C down starting at the carboxyl or α end.
What are the steps in α oxidation?
PHYTOL (α hydroxylase)to PHYTANIC ACID (phytanic acid α oxidase)to PRISTANIC ACID to PROPINOYL COA (3 C CHAIN)
Which enzyme deficiency results in Refsums's diesase?
α hydroxylase is deficient causing bulid up of phytanic acid
Where is phytol found?
in green leafy veggies
What happens if fatty acids are not used?
Micelles will form around them and breakdown the cell membrane :(
What does ω oxidation accomplish?
oxidize the ω C (methyl group)to a carboxyl group to a dicarboxylic acid or a monocarboxylic acid (fatty acid)
What is the point of forming a ω oxidation?
Get fatty acids out of the cell so the membrane is not destroyed
What is P450's role in ω oxidation?
it hydroxylates the ω C, preparing for dicarboxylation
What happens in dicarboxylic aciduria?
VLFA build up becuase of a defective acyl CoA dehydrogenase
Is the ω oxidation pathway significant in long chain or medium chain FA's?
More significant in medium chain FA's
What is anothe name for dicarboxylic aciduria
NON ketotic acidosis
What are some possible reasons for dicarboxylic aciduria?
carnitine deficiency, CPT1/2 uptake mechanism troubles, defective MCAD (medium chain acyl dehydrogenase).
All increase the VLFA's
Where does ω oxidation occur?
in the ER
Which enzyme is used in mono and poly unsaturated fatty acid oxidation? What does this enzyme do?
2,3 enoyl CoA isomerase
transfers cis to trans in order to complete beta oxidation
How many enzymes are involved in monounsaturated and polyunsaturated FA oxidation?
1 in mono
2 in poly
Which enzymes are used in polyunsaturated FA oxidation? What do they do?
2,3 enoyl CoA isomerase (takes cis to trans)
2,4 dienoyl CoA reuductase (reduces one more bond)
Which ABC enzyme is used in the porpinolyl CoA pathway? Where does it come from?
propinooyl coA carboxylase
from phytol and bile salt breakdown
Which vitaman is extremely important in the propinoyl CoA pathway? What happens when there is a deficiency of this enzyme?
A deficiency will generate methylmalonic acid urea
Which enzyme is requires B12?
methylmalonyl CA mutase
What is the difference between methylmalonyl Coa and malynoyl CoA?
MALYNOLY CoA is used in fatty acid synthesis keeps FA out of the mitochondria while FA synthesis is taking place. Acetyl CoA to 3 C malyonyl CoA to FA

METHYLMALONYL CoA is used in teh propinyl coA pathyway leads to succinyl CoA (Step requires b12)
If it is found that a person has a defect in fatty acid oxidation what therapy can be utilized?
never go into fasting state
What happens in a newborn with MCAD deficiency and why can it go undetected?
it is not screened for as is PKU. Baby can survive fine until it has to undergo gluconeogenesis and enter beta oxidation. medium chain acyl dehydrogenase deficiency leads to inability to breakdown FA's and FA's breakdown the cell membrane
Where is HMG CoA synthase found?
In cytosol of all cells, but in mitochondrion of LIVER in order to form ketone bodies
What is the pathway of keotgenesis?
Acetyl CoA to (THIOLASE)Acetoacetyl CoA to (3 HMG COA SYNTHASE)3 hydroxy3methylglutaryl Co, AKA, HMG CoA to (HMG LYSASE)acetoacetate to (SPONTANEOUS)either acetone or to (Dβ-HYDORXYBUTARYATE DEHYDROGENASE)
What usually happens with acetone?
it is expired either thru air or urine
What happens when abnormal amounts of acetoacetate and Dβ-hydroxybutyrate are formed in abnormal amounts?
high levels result in ketoacidosis
Where do ketone bodies come from?
Breakdown of fats
Are ketone bodies water soluble?
Yes, so they travel easily through the blood
Where are ketone bodies formed predominantly?
In the liver
which tissues prefer ketone bodies as an energy source regularly? During the starved state?
Cardiac and renal cortex

During starvation: brain and mm
Which reaction of ketolysis is spontaneous?
acetoacetate to acetone
What leads to ketoacidosis?
uncontrolled diabetes or starvation
Where does ketogenesis take place?
Within the cell--in the liver inside the mitochondrion, in all other cells in the cytosol(sterols)
Where is HMG-Co lyase found?
ONLY in the mitochondria
What oxidizeing fatty acids NADH is increased what happens as a result of this?
beta hydroxybutyrate is formed as a result of high NADH to NAD
What is the primary source of ketone bodies?
the liver b/c only liver mitochondria have large amts of HMGCoA synthase
What happens in ketolysis?
Basically the reverse of ketogenesis just different enyzmes

From beta hydroxybutyrate (D
Where is ketolysis performed?
What's interesting about the beta hydroxybutyrate dehydrogenase reaction?
It is very reversible
Wheich enzyme catlyzes the acetoacetate to acetoacetyl CoA rxn? Where is it found? What does it allow for?
IMPORTANT: Beta keto co A transferase

Found in the mitochondiral matrix of most tissues--EXCEPT IN THE LIVER

Allows for breakdown of ketone bodies.
Under normal conditions what is the brain using as a source of energy?
Using 90% glucose and 10% Ketone bodies normally.
Five days into starvation what is the brain using as a source of energy?
50% glucose 50% ketone bodies (at this time FA are broken down but cannot cross the blood brain barrier)
How many days into fasting will gluconeogenesis support an organism? Where does energy come from?
5 days to a week. Source is glycogen for about a day then protein is broken down until the end of the 1st week when fat stores start to break down.
What form of energy takes over after gluconeogenisis is over? Why is this important?
Ketone bodies take over after 5 days of starving. This is important because don't want to deplete protein. Ketone bodies mobilize fat stores for energy.
How long can a person survive while starving (with water)?
About 72 days after that protein in heart and lungs is depleted and cardiac or pulmonary arrest ensues
What does gluconeogenesis NEED?
ATP via breakdown of fatty acids or protein or glycogen
What happens to the TCA cycle in diabetes or fasting?
slow the TCA cycle by drawing off of OAA to enhance acetyl CoA to acetoacetate
What is acetyl CoA important in?
Everything--TCA, B oxidation of fatty acids
What are symptoms of diabetics?
hyperglycemic (low insulin), fatty liver, FA in blood causes diauretics, increased urination, emaciated, high BUN blood urea nitrogen
What happens in a grazing diet?
It's good for you, don't have swings between glucogon and insulin worlds.
What happens when people overeat?
increased carb leads to increased fat leads to being obese because hexokinase is turned off in mm cells, signal transduction shuts down the insulin response and now you have dietary induced diabetes
What happens in the starvation state?
Breakdown fats and proteins for energy. Loose weight rapidly. have to be careful when exercising. No extra glucose to go into the glucogon world. Go into hypoglycemic shock.
What happens in the atkins diet
increase protein to try to protect against protein loss. Try to protect against mm and tissue breakdown. Have to stay hydrated so kidney's aren't damaged by amino acid excretion and take care when exercising. try to make all sugar from protein.
What's the difference between type I and type 2 diabetes?
Type 1 can't make insulin
Type 2 can't use it

Always in the glucogon world
What does insluin do?
lowers blood glucose levels
What is insulin made of?
A protein made of A and B chain polypeptides, which are linked by disulfide bonds, and a C peptide
How is proinsulin activated? Mature insulin?
Preproinsulin is converted to proinsulin by adding three disulfide bonds and removal of signal sequence.

Proinsulin is converted to mature insluin by clevage of the C peptide at the time of secretion.
Where is insulin synthesized?
In the pancreas beta cells as preproinsulin
Where are disulfide bonds formed?
Between a and b chains of proinsluin.
How can compliance be checked in a diabetic patient on insluin?
Check for ratio of insulin to C peptide. c peptide should be lower because the patient does NOT receive it in the mature form of insulin (not 1:1)
How is glucogon formed?
formed from larger precursor protein preproglucagon to proglucogon by prteolytic cleavages
Where is somatostatin produced? What does it do?
12AA PP synthesised by delta cells of pancreas in intestinal cells and hypothalamus.

Inhibits secretion of insulin AND glucagon
Where are water soluble molecules combine with the cell?
outside of the cell. Usually affect metabolism mor ion channels
Where do water INsoluble molecules combine with the cell?
Inside the cell (non-polar molecules). Can cross membrane by signal transduction. Insulin and glucogon are examples. Affect transcription regulation
Is insulin required for the uptake of glucose?
Yes, which is why diabetics cannot do so.
What are fasting blood glucose levels in mg/dL and mM?
80-90 mg/dL
4-5 mM
Where are GLUT 2's found?

blood glucose sensors
In the hepatocyte when epinephrine is working which receptor is it affecting?
alpha 1
Beta 2 is also in the hepatocytes, but alpha 1 predominates.
Are fatty acids converted directly into glucose in the glucogon world?
No!!! FA's are used to create an energy source so that gluconeogenesis can proceed.
How does chymotrypsin work? What is the starting point?
Chymotripsinogen (inactive) is worked on by Trypsin to form pi-chymotrypsin which is active. The activated chymotrypsin then works on itself to make another break in the peptide to form alpha chymotrypsin.

Which form of chymotrypsin is more active?
alpha chymotrypsin is more active (than pi chymotrypsin)
Where is enteropeptidase found? What does it do?
Found on gut wall

Very important role. Activates zymogen trypsinogen in order to activate all the other zymogens
What would happen if the gut lining was damaged?
Enteropeptidase is damaged then cannot breakdown proteins in the gut, other enzymes won't work
Do proteases demonstrate specificity?
Yes they do. Ex. chymotrypsin recognizes aromatics and Leucine on the N terminus of the peptide relative to the sissle bond, the sissle bond is on the carboxy side.
What is meant by positive Nitrogen balance? Negative nitrogen balance?
Positive in the insulin world bring N in. Negative in the glucogon world breaking down proteins.
What does trypsin break down?
chymotrypsinogen, proelastase, procarboxypeptidases. Breaks down zymogens and leads to a cascade effect after activated by enteropeptidase
Where does the urea cycle get nitrogen from?
What are the pathways glutamate can take to get to the urea cycle?
Ends up as either ammonium (NH4) or as aspartate
How does transamination usually work?
TRANSFER a N as an amino group from the ORIGINAL AA to ALPHA KETOGLUTARATE to form GLUTAMATE.

The ORIGINAL AA is converted to its corresponding ALPHA KETO ACID

What is an alph keto acid?
an amino acid w/o it's amino group. Formed during transamination
What happens to an alpha keto acid in transamination?
an aa loses its amino group and forms an alpha keto acid (AKA). The amino group reacts with another alpha keto acid to form an aa.

tranfer of amino group from one aa to another via AKA's
What does SGPT, formerly ALT stand for? What does it do?
Serum glutamate pyruvate transaminase.

Forms pyruvate AND glutamate from alanine
What does SGOT, formerly AST, stand for? what does it do?
Serum glutamate oxaloacetate transerase.

Transfers aspartate to glutamate and OAA
Is glutamate and intracellular carrier or donator of N?
Glutamate is an intracellular carrier of N.
Which alpha keto acid is used in SGOT and SGPT rxns?
alpha keto glutarate
How many C's do the following have:
Alanine 3C
Aspartate 4C
Glutamate 5C
Why are SGOT and SGPT levels measured?
Because indicates heart damage. Monitored in recovery
What is pyridoxal phosphate? What does it do? What vitamin is it associated with?
PLP is a prosthetic group that functions as an intermediate carrier of amino groups at the active site of aminotranferases. It is a derivative of vitamin B6.
How do aa cross the gut or the kidney and enter the blood?
Via transporters, mostly Na dependent transporters
some facilitated transporters
What is concentrateion dependent on?
volume inside cell is much less than volume outside the cell
What does arginine resemble?
Urea, so it will be found in the urea cycle
What is transDEamination?
What is an example of this?
The combination of aminotransferase AND glutamate dehydrogenase

Ex. Taking glutamate to ammonium ion
Where is glutamate dehydrogenase found (GDH)
in the mitochondrial matrix
How is ammonium generated?
By D and L amino acid oxidase

Occurs in peroxisomes because H202, a keto acid, and an ammonium ion are formed
What happens in the hydrolysis of glutamINE and asparagINE?
Add water to yield ammonia and aspartATE OR glutamATE via either glutaminASE or aspargenASE
How many N's does glutamine carry?
What occurs in the reaction with glutamine synthetase? What are the reactants and products?
Use ATP AND NH4 (ammonium ion) to transform glutamate into GLUTAMINE, inorganic phosphate, and ADP. Used in nitrogen waste disposal.
Do kidneys have a high level of glutamine? Why or why not?
Yes. The kidney performs a hydrolysis reaction with glutamine to create ammonia in a state of acidosis. Yes, ammonia is toxic, but here ammonia is used to neutralize the acid. It forms ammonium which is not toxic and is excreted.
Do intestinal cells have high glutamine levels? Why or why not?
Yes, they do but for a different reason than the kidney cells. Here the increased glutamine is used as a precursor to nucleotides which are necessary to replace the frequenly replaced intestinal cells
What are the normal blood levels of ammonium and ammonia? Which is the acid?
ammonium (the acid) 0.5mg/L
ammonia is 0.005mg/L or 5ug/L
What is the pka for ammonium?
What is the limit for ammonia before it becomes toxic?
10ug/L --- not too far from normal (5ug/L)
Which urea cycle enzymes are found in the mitochondria?
1. Carbamyl phosphate synthetase I (CPS I)

2. Ornithine transcarbamylase

3. N acetyl glutamate synthetase
What is the overall rxn for the urea cycle?
NH4 + HCO3 + Aspartate + 3ATP + H20 = Urea + Fumarate +2ATP + 2Pi + AMP + PPi
What is the rate limiting step in the urea cycle? What stimultes the enzyme?What is the rxn?
carbamoyl phosphate synthetase I (CPS I)

N acetylglutamate stimulates (CPS I)

Forms carbamoyl phosphate from N acetylglutamate.
Where does N-acetylglutamate
come from?
From acetyl coA and glutamic acid via NAGS (N acetyl glutamate synthetase)
What is the job of citrulline? Or ornithine?
Carriers between mitochondria and cytosol.
Citrulline carries out of mitochondrion and ornithine carries into the mitochondrion.
How does the urea cycle flow from carbamyl phosphate?
carbamyl phosphate (OTC)to citrulline to aspartic acid to arginiosuccinic acid to fumaric acid to arginine to orthine OR urea (via arginase)
Is CPS I part of the urea cycle?
No, not really. It feeds carbamyl phospate into the cycle (like PDH does into the TCA cycle) It is needed for the cycle, but not actually in the cycle.
What are the common symptoms in hyperammonemia I and II, which is which, and what are the differences?
In both types of hyperammonemia you get increased glutamic acid, increased ammonium and decreased BUN. Also, get cerebral edema, lethargy, convulsions, death.

Hyperammonemia I is a problem resulting in Ornithine transcarbamoylase and results in INCREASED URACIL AND OROTIC ACID in the blood and urine.

Type II hyperammonemia results from a deficiency in carbamoyl phosphate synthetase WITHOUT the increased orotic acid.

Main difference is orotic acid (found in type I with OTC deficiency)
What does OTC deficiency cause?
Causes increase in carbamoyl phosphate which bleeds into the cytosol. Rxn of carbamoyl phosphate with CPS II produces orotic acid and Uracil for pyrimidine synthesis
Is a COMPLETE block in the urea cycle compatible with life?
What symptoms will all patients have when there is a block anywhere in the urea cycle?

What is the treatment? Why?

treat with alpha ketoglutarate a keto acid which provides glutamate to use in the urea cycle.

and low protein diet
How many aa's are found in every protein?
All 20
Which essential aa is required during growth?
What is meant by negative nitrogen balance?
nitrogen excretion exceeds nitrogen intake. Common in infections, burns, postsurgical stress and increased glucocorticoid secretion from the adrenal cortex
What happens in nitrogen balance?
nitrogen excretion is equal to nitrogen intake. In healthy adults this is true
Who is likely to exhibit positive nitrogen balance?
Pregnant women and growing children. Nitrogen intake is greater than nitrogen excretion
What is notable of leucine?
It is ONLY ketogenic. Not glucogenic.
What does glucogenic mean? ketogenic?
glucogenic have ability to make glucose.

ketogenic used to make ketone bodies through acetyl coA--remember can't do work with acetyl coA once it gets into the tca cycle
What happens in cystinuria?
How can you diagnose it?
cystINE least soluble of naturally occuring aa.

leads to kidney stones caused by problem with reabsorption.

kidney stones, then check for lysine ornithine and arginine which are basic acids that are tranported by the same transporter as cystine.
What is the treatment for cystinuria?
lots of fluids and decrease cystine intake
What's the difference between cystine and cysteine?
cystine is 2 cysteines linked by a disulfide linkage
Symptoms such as hypercoagulation and thrombosis (DVT)could be associated with which amino acid disorder?

What is the biosynthetic reason for this disorder?

What deficiencies could cause this disorder?
Homocystinuria--in high levels in the blood can activate blood coagulation proteins.

caused by a deficiency in CYSTATHIONINE SYNTHASE (PLP DEPENDENT) which normally takes homocysteine to cystathione to propionyl CoA pathway.

B12 or Folic acid deficiencies can be nongenetic causes.
Which enzymes feed into the propionyl coA pathway?
VOMIT--valine, or methionine isoleucine, theronine
What are the two important enzymes that get homocystine to the propionyl CoA pathway?
cystathionine synthase and lyase
What is the difference between methionine and homocysteine?
Just a methyl group on methioine.
What does a deficiency in cystathionine LYASE lead to?
Leads to cystathioninuria. Less common than homocystinuria
What are the three branched aa that are not degraded in the liver?

How are they degraded?

Which enzyme degrades them in the liver?

What happens when there is a deficiency in this enzyme?
Valine, Isoleucine, Leucine (gaLIVp)

degraded extrahepatically to alpha keto acids so they are polar and can be transported in the blood.

alpha keto acid dehydrogenase breaks down the alpha keto acids in the liver

A deficiency of this enzyme leads to maple syrup uria because the alpha keto acids have a sweet smell in the urine
Is PKU common?
Yes it is teh MOST common inborn error of AA metabolism
What causes PKU?

What forms as a result?
deficiency of phenylalanine hydroxylase.

can't break phenylalanine down to tyrosine so (it increases)then undergoes phenylalanine transamination to phenylpyruvate which leads to increase of phenylacetate and phenyllactate in the blood. Called phenyl ketones, create problems within the cell.
What must PKU patients avoid?

What does PKU stand for?

How is it treated?
Anything containing phenylalanine, such as aspartame in nutrasweet.

PKU= phenylketonuria

Treated with a synthetic diet lackin phenylalanine
What are the symptoms?
Normal infants at birth. Prenatal testing can detect. Leads to hyperactive deep tendon reflexes, hyperactivity and mental retardation.

Blood analysis indicates elevated phe (1.2mM) normal tyr
What does PLP require?
Vitamin B6
What do strict vegans need to be aware of when they are pregnant? What could result if they aren't?
B12 deficiency. Her baby could have megloblastic deficiency with homocystineuria, cytathioninuria and methylmalonic aciduria
What causes cystahioninuria?
cystathione lyase deficiency
What are the three signs of alkaptonuria?
the triad of alkaptonuria:
dark urine
ochronois--dark joints
What are characteristic of megaloblastic anemic cells?
impared DNA synthesis, usually in cells that have a rapid turnover--esp hematopoietic precursors and gastrointestinal epithelial cells.

Cytoplamic development is normal but cell division is not.

Megaloblastic cells are large with more RNA than DNA
What is the cause of most megaloblastic anemias?
B12 or folic acid deficiencies
What is SAM's job?

to what?
to donate methyl groups

to make

N-methylguanine cap on mRNA
phosphidyl choline
Where is succinyl coA found and what does it do?
Can be generated from propionyl CoA pathway and is found in the TCA cycle and is important in heme synthesis
Where does propionyl CoA come from?
it is cleaved from cholesterol or minor from odd carbon fatty chains
What does methyl malonyl CoA mutase do? What 4 other things also do the same job?
transfers methyl groups

1. folic acid
2. B12
3. methionine
4. SAM
Which 2 reactions use vitamin B 12?
methylmalonyl CoA mutase--get methylmalonic urea diagnositic for B12 deficiency

homocystine methyltransferase
ties methionine to folic acid metabolism. Uses B12 AND folic acid.
What happens in a methylmalonyl CoA mutase deficiency and what is its importance?

Which two metabolism paths does homocystine methyltransferase tie together? What does it require?

What does homocystine methyltransferase use?
get methylmalonic urea--diagnositc tool in B12 deficiency
Ties methionine and folic acid metabolism together

Requires B12, B6 and folate
How are the analogs of folic acid formed?
by methyl transfer via formate

N10 formyl FH4
N5, N 10 methyenyl FH4
N5, N 10 methylene FH4

a pool of active folate derivatives
What is folic acid important for?
How do sulfa drugs work? What is the significance with respect to folic acid?
Bacteria break synthesize folic acids, but cannot when a S is introduced (competitive inhibition of PABA). Can no longer produce DNA from RNA and bacteria die. Humans don't synthesize folic acid so this drug is useful in killing bacteria.
What does thymidylate synthase do?
Takes dUMP to dTMP by transfer of methyl from dihydrofolate to tetrahydrofolate to N5, N10 methylene FH4 with thymidylate synthase forms dTMP.
What inhibits thymidylate synthase? What inhibits dihydrofolate reductase?
5 fluorouracil inhibits thymidylate synthase.

Methotrexate inhibits Dihydrofolate reductase.
What are the 2 enzymes involved in the rxn of dUMP to DTMP? What do the U and T stand for?
thymidylate synthase and methotrexate.

U for uracil and T for thymine--RNA to DNA!
What happens if thymidylate synthase is inhibited?

What is a use for methotrexate?
No more cell division--death.

Methotrexate is used as a cancer therapy; chemotherapy

shuts down cancer cells
When methotrexate is used in chemotherapy why doesn't it kill ALL cells?
This is why dosage is so important. Methotrexate will affect the rapidly dividing cancer cells MORE so than other, but still suceptible to damage which is why hair falls out and gut cells are irritated (nausea and vomitting).
What is the difference between prenicious anemia and megaloblastic anemia?

Could a person have prenicious anemia AND megaloblastic anemia?
Prenicious anemia is DUE TO VITAMIN B 12.

Yes a vitamin B12 deficiency could lead to a folic acid deficiency.
What happens in a prenicious anemia?

What can cause this?

How is it treated?
results in the inability to produce an intrinsic factor.

Either born with it or aquired with age--lose the abitlity to produce the intrinsic factor in the stomach (gastric parietal cells). This leads to malabsorption of B12

Treatment: B12 shot once every 3 months (liver supplies last about that long) CANNOT TREAT ORALLY--MUST BE IV B/C GASTRIC PARIETAL CELLS ARE AFFECTED!!
What is cobalamin?
Vitamin B12
What is diagnostic of cobalamin deficiency?
methylmalonic aciduria

also same symptoms as folate deficieny: megaloblastic anemia, homocystinuria
What diseases are caused by abnormalities in purine metabolism?
1. Lesch Nyhan syndrome
2. adenosine deaminase deficiency
3. Purine Nucleoside phosphorulase deficiency
Which types of dysfunction are more likely, pyrimidine or purine metabolism? Why?

Name a pyrimidine disease.
Purine metabolism results in more defects. Pyrimidine products are more soluble and can be excreted.

Pyrimidine problem: orotic aciduria
Are there essential nucleotides?
no, we can produce them de novo
What aa are used in the biosynthesis of purines and pyrimidines?

Which is exclusively for purines?
Aspartate, Glutamate and Glycine

Glycine is exclusive to purines
What is N methyl THF used for?
Trapped or Storage form of folate

rxn catalyzed by homocysteine methyl transferase uses N methyl THF to free useful form THF
What is PRPP? What is it used for?
5 PhosphoRibosyl 1 PyroPhosphate

Used in purine and pyrimidine biosynthesis. The purine or pyrimidine is formed and then added to PRPP to either undergo de novo synthesis or to be salvaged
Where is carbamyl phosphate synthetase II (CPSII) found and what does it use to make carbamyl phosphate?
CPS II found in the cytoplam and uses glutamine
Describe the synthesis of pyrimidines
Glutamine (CPS II)to carbamoyl phosphate REQUIRES ASPARTATE(transcarbomylase)to carbamoyl aspartic acid to orotic acid to UMP TO UDP to (by ribonucleotide reductase)dUDP to dUMP (thymidylate synthase)to (via cycle of DHF to N5N10 methylene THF thru dihydrofolate reductase)dTMP
What inhibits dihydrofolate reductase?
in eukaryotes methotrexate
in prokaryotes trimethoprim
in protozoa pyrimethamine
In addition to sulfa drugs what else can be given to inhibit nucleotide synthesis in bacteria?
trimethoprim inhibits dihydrofolate reductase in bacteria and will inhibit nucleotide synthesis resulting in death
What inhibits ribonucleotide reductase?
hydroxyurea--another antineoplastic not frequently given
Which two aa are necessary for pyrimidine biosynthesis
glutamine and aspartate
What activates aspartate transcarbamoylase? Inhibits?
ATP activates
CTP inhibits (cytidine tri phosphate)
What inhibits thymidylate synthase?
5 flurouracil
What are symptoms of orotic aciduria?
elevated orotic acid, no associated hyperammonemia!!
What is ionisne MP made of?
ribose and hypoxantanine
Describe the de novo synthesis of purines.
start with ribose 5P from the HMP shunt (PRPP synthetase)to PRPP to (via regulated enzyme PRPP glutamyl amidotransferase)5 phosphoribosylamine add on glycine aspartate glutamine (glycine only for purines, add THF for C donor leads to IMP which forms either AMP or GMP
What regulates purine biosynthesis? What enzyme do they work on?
Its end products: GMP AMP and IMP they work on PRPP glutamyl amidotrasferase. Also allopurinol and 6 mercaptopurine nucleotide
What is the key regulatory step in purine biosynthesis? What are the basics of the biosynthesis in terms of sugar, P energy??
PRPP glutamyl amidotransferase

start with the sugar (ribose 5P), Add PRPP for phosphates, form a purine ring using AA (glutamine, aspatate and glycine), Folic acid is added for C's. the process uses ATP, so AMP, GMP, and IMP are ihibitors of the rxn. Once ATP is used up, then nucleotides have been formed and stop!
Which enzymes are of clinical importance in the degradation or salvage pathway of purines?
1 adenosine deaminase results in severe combined immunodeficiency SCID. BUBBLE BOY

2 Purine nucleoside phosphorylase results in selective T cell immunodeficiency

3 Xanthine oxidase

4. HGPRT hypoxanthine guanine phosphribosyltransferase results in Lesch-nyhan syndrome
Describe the purine degradation or salvage pathway.
Take biosynthetic inhibitors and break them down (or make energy out of them)by dephosphorylating AMP and GMP. AMP breaks down to adenosine and a NH3 group is cleaved by adenosine deaminase to give inosine. GMP breaks down to guanosine. From here both lose a ribose P by pruine nucleoside phosphorylase to form inosine to hypoxanthine and gluanosine to guanine. Then 90% is salvaged by HGPRT to lead back to the biosynthesis inhibitors GMP and IMP. The other 10% are converted to xanthine and via canthine oxidase they're converted to uric acid and excreted.
What causes gout?
deficiency in HGPRT.
low nucleotide pool
decrease feedback
increase nucleotide synthesis
increase degradation
increase uric acid
form cyrstals
gouty arthritis
How is gout treated?
With allopurinol inhibits xanthine oxidase AND (minimally)inhibits PRPP amidotransferase of biosynthesis to help decrease the uric acid. This is because it looks like IMP and GMp whne it is added to a sugar (looks like a nucleotide)

Remember the more you produce the more you degrade
What does allopurinnol inhibit? act as a substrate for?
Inhibits xanthine oxidase, so xanthine and hypoxanthine and uric acid are increased. Increased excretion.

Substrate for HGPRT
What causes Lesch Nyhan? Who gets it?
HGPRT deficiency.

Males predominantly because it is an X linked recessive disease.

Causes severe mental retardation in young boys. Chew their hands.

In older men only a partial blockageleads to gouty arthritis
What is the use of 6 mercaptopurine?
It is an antineoplastic and used as a chemotherapy. Inhibits PRPP amidotransferase and shut down cancer cells.