What enzyme is inhibited by Methotrexate?

5-Flurouracil?

Dihydrofolate reductase (reduction of DHF to THF)

and

Thymidilate synthase (dUMP to dTMP)

Which form of folate is use to synthesize dTMP?

N5,N10 methlene THF

Dwaw out the synthesis pathway for dTMP

see image

Why is one important suppliment pregnant women should take in the 1st and 2nd month of pregnacy?

Why?

Folic Acid.

Folic acid reduces the risk of neural tube defects, particularly spina biffida and anencephaly.

What is SAM?

Why is it imporant?

S-adenosyl methionine.

SAM is the primary donor of single carbon groups (methyl, methylene, methyne) in biological reactions.

What AAs are important in cysteine synthesis?

From what substrates are the -SH group and the C derived?

Methionine, and Serine.

Methionin (via homocystein) is the source of the -SH

Serine provides the carbon backbone for cystein.

What enzyme catalyzes the reaction in which SAM is formed?

What are the substrates in this reaction?

Methionin adenosyltransferase.

Methionine and ATP

What is 5-flurouracil?

Why is it important?

5-fluorouracil is a popular chemotherapeutic agent, that inhibits the activity of thymidilate synthase, and therefore DNA synthesis

(dUMP to dTMP)

Dihydrofolate reductase is inhibited by what drug?

What reaction does dihydrofolate catalyze?

Methotrexate

FH2 to FH4

NorEpi to Epi

Guanidoacetate to creatine

phosphatidyl ethanolamine to phosphatidyl choline

acetyl seratonin to melatonin

What do these reactions have in common?

they all require SAM as a methylating cofactor 

decrease in new RBC synthesis due to faulty thymidine synthesis.

caused by B12 deficiency, most often due to intrinsic factor or B12 uptake deficiency.

Pryimidine synthesis

The reaction (N5,N10-methlene THF to N5-methyl THF) is irreversible; so if N5-methyl THF is not being utalized cellular levels of N5,N10 methlene THF will not be efficiently regenerated.

N5,N10 methlene THF is necessary for thymidine synthesis

B12 and/or homocystein methytransferase deficiency.

Hyperhomocysteinuria/homocysteinuria is caused by a deficiency in B12-mediated regeneration of methionine from homocystein. it can be caused by a B12 vitamine deficiency or a faulty homocystein methytransferase enzyme.

you could treat homocysteinuria with supplimental B6 (pyrodoxal phosphate is the cofactor for cystatione synthase which removes homocystein)

N5-methyl THF.

N5,N10-methenyl THF

Is glycine an essential amino acid?

If not what it is substrates contribute to its synthesis?

No.

Glycine is synthesized when Serine is used to synthesize N5,N10-methylene THF from THF

Are Isoleucine, Valine and Methionine glycogenic?

If so what do they break down into?

propionyl CoA to methylmalonyl CoA to Succinyl Coa (TCA cycle intermidiate)

All are Glycogenic

What is a nucleoside?

A nucleotide?

nucleoside is the base plus a ribose sugar.

a nucleotide is the nucleoside phosphate ester.

What is the primary substrate for purine synthesis?

What enzyme produces this substrate?

What is the 1st enzyme in this pathway?

What is the product of this reaction?

Pruine biosynthesis begins with Ribose-5P an intermidiate in the Pentose phosphate pathway.

Ribose-5P is produced from 6-Phosphoglutarate by 6PGDH.

PRPP synthase

the product of this reaction is 5-phosphoribosyl pyrophospate (PRPP)

IMP, GMP, and AMP inhibit which enzymes in the purine synthesis pathway?

PRPP synthase, and amido-phosphoribosyltransferase

classic product inhibition.

APRT catalyzes the conversion of PRPP into  the first intermidiate in the synthesis of IMP.

Glutamine (becomes glutamate), and PRPP

Draw the purine synthesis pathway.

Is glutamate an essential amino acid?

Describe the regulation of GMP and AMP formation.

What is the primary substrate?

GMP synthesis is catalyzed by ATP and Glutamine. Inhibited by GMP

AMP synthesis is catalyzed by GTP and aspartate. inhibited by AMP

What are the two metabolic pathways for the purine nucleosides after RNA degradation?

What are the terminal products of these pathways?

Metabolic degradation to Uric acid,

purine salvage pathway to form IMP

Name the enzymes that catalyze the conversion of free nitrogenous bases to substrates usable for nucleoside synthesis.

What is the name and the biochemical cause of the self-destructive disorder associated with a deficiency in purine salvage?

Adenine to AMP (anenine phosphoribosyl transferase)

Guanine to GMP

(Hypoxantine-Guanine phosphoribosyl transferase)

Hypoxanthine to IMP

Lesh-Nyhan Syndrome. Deficiency in HGPRT is believed to deminish the sensation of pain leading to this disease

What causes gout?

What are the primary symptoms?

What would be observed in a patient with gout?

Buildup of Uric acid in the blood serum causes sodium/calcium to precipitate out of solution forming crystals which accumulate in the joints, particularly that of the great toe.

Intense pain in the joints

Inflammation, edema, and a join that is warm to the touch

What are the purines? The pyrimidines?

Draw the purine synthesis pathway

Purines: Adenine, Guanine, Hypoxanthine

Pyrimidines: Thymine, Cytosine, Uracil

See image

What is Xanthine oxidase?

What is the theory behind xanthine oxidase and reperfusion injury?

Xanthine oxidase catalyzes the conversion of Hypoxanthine to Xanthine to Uric acid in the purine catabolism pathway.

Xanthine oxidase can produce oxygen anion radicals which are ROS.

Describe the function of allopurinol.

Why might cholchicine be an effective treatment for gout?

Allopurinol is a xanthine oxidase inhibitor, and is used to treat patients with gout.

Allopurinol causes xanthine and hypoxanthine to accumulate in the blood (both of which are more soluble that uric acid), which will then be excreted.

Chochicine inhibits the actin/myosin interaction important for leukocyte migration which is the basis for the inflammatory response.

Coenzymes (FAD, NAD, CoA)

ATP

2nd Messengers (cAMP [Adenyl Cyclase])

What are the key differences between CPSI and CPSII?

What are the substrates and products in the reaction catalyzed by CPSII?

Regulatory Factors?

CPSII is active in all tissues.

Substrates: Glutamine (nitrogen) and CO2 (carbon)

Products: Carbamoyl phosphate

UTP (-)

Pyrodoxal Pyrophosphate (+)

What enzyme catalyzes the synthesis of carbamoyl aspartate?

What are the substrates of this reaction?

What regulates the actvity of this enzyme?

Aspartate transcarbamoylase. r(t) limiting enzyme in pyrimidine synthesis.

Aspartate and carbamoyl phosphate.

CMP,CDP,CTP

Describe the structure and function of the enzyme ribonucleotide reductase.

Describe the global regulation of RR.

Ribonucleotide reductase is a complex dimeric enzyme with 2 substrate binding sites and 4 allosteric sites.

dATP deactivates ribonucleotide reductase

Draw the pathway from NADPH to deoxyribonucleotide catalyzed by ribonucleotide reductase.

What role does Thioredoxin play in this pathway?

What enzyme catalyzes the reaction involving thioredoxin?

(See image)

Thioredoxin is an electron carrier, it ferries e- from NADPH to the -SH groups within the catalytic site of RR.

Thioredoxin reductase.

Describe the etiology of SCIDS.

Sever combined immunodeficiency synrome is a congenital disorder affecting the enzyme adenosine deaminase which converts dATP and ATP to hypoxanthine and xanthine.

Ribonucleotide reductase is chronically inhibited in these individuals resulting in decrease leukocyte and macrophage production, and immunodeficiency.

Amino Acids can be glucogenic, keogenic or both.

Name the amino acids that are exclusively ketogenic, as well as those that are both glucogenic and ketogenic

Exclusively ketogenic: Leucine, Lysine

Both Ketogenic and glucogenic: phenylalanine, tyrosine, isoleucine, tryptophan

What is the significance of homogentisic acid?

What is the precursor of homogentisic acid in its metabolic pathway?

What is the name of the enzyme that is deficient in the disorder associated with homogentisic acid?

Alcaptonurea is a congenical metabolic disorder associated with excess homogentisic acid in the urine, which turns black when exposed to air.

Tyrosine. The pathway begins with Phenylalanine to Tyrosine to homogentisic acid to fumarate and acetoacetate

(tyrosine and phenylalanine are ketogenic and glucogenic.)

Homogentisic acid oxidase.

The metabolism of phenylalanine to tyrosine is inhibited in what congenital disorder?

What enzyme is impacted?

What symptoms are associated with this disease?

Phenylketonurea.

phenylalanine hydroxylase.

Progressive neurological disease, and eventuall death if untreated.

Leucine is ketogenic glucogenic or both?

What is the terminal product of leucine metabolism?

Leucine is exclusively ketognic.

Leucine to HMG CoA to Acetoacetate (Ketone Body)

What AAs are metabolized to form Acetyl CoA?

Acetoacetate?

HMG CoA?

Threonine, Lysine, Isoleucine, Tryptophan

Phenylalanine, Tyrosine

Leucine

Four Amino Acids are metabolized into Succinyl CoA, list them?

Draw out the pathway for metabolism of the Succinyl CoA family.

Methionine, Threonine, Isoleucine, Valine

(see image)

Six amino acids are ultimately metabolized into pyruvate. What are they called, and how are they related?

What is special about Threonine?

Are these AA glucogenic?

Tryptophan, Alanine, Glycine, Serine, Cystein, Threonine

Threonine metabolizes into acetoacetone and then into pyruvate.

What AAs metabolize into Fumarate?

Are any of these AA ketogenic? If so Which ones?

Oxaloacetate is produced from which AAs?

Draw the pathway.

Asparagine to Aspartate (asparaginase)

Aspartate to OAA (GOT Transaminase)

Can Mammals produce Pyruvate from Acetyl CoA?

If so describe the pathway.

How many enzymes are metabolized to alpha-ketoglutarate?

Draw the pathway.

What is the final AA in this pathway before the conversion to aKG?

5. (Histidine, Arginine, Proline, Glutamine, Glutamate)

See image

Glutamate

Histidine can be used to synthesize a substrate in the folate biosynthesis pathway. Which one?

What important THF substrate is in and equivalent oxidation state?

N5,N10 Foramino THF

N5,N10 Methenyl THF

The urea cycle involves arginine how?

What enzyme catalyzes this reaction?

What are the products of this reaciton?

Arginine to Ornithine + Urea

Arginase

Ornithine and Urea. Ornithine then reenters the Urea cycle

Glutamine can be used to synthesize Glutamate. What enzyme catalyzes this reaction?

What pathway is coupled to this catabolism of glutamine?

What are the substrates and products of this reaction in the associated pathway?

amido-phosphoribosyltransferase

Purine Synthesis.

Phosphoribosyl pyrophosphate to 5-phosphoribosylamine

What AA would need to be included as a suppliment for individuals affected by PKU?

What enzyme is nonfunctional in these individuals?

Tyrosine.

Phenylalanine hydroxylase; which catalyzes the reaction converting Phenylalanine to tyrosine.

What are the BCAAs?

What is the significance of Acyl CoA Dehydrogenase here?

What products does it form?

Valine, Isoleucine, Leucine

Acyl CoA dehydrogenase catalyzes the final reaction in the metabolism of BCAAs. Maple syrup urine disease is caused by a deficiency in this enzyme.

Propionyl CoA (Valine, Isoleucine)

Acetyl CoA + Acetoacetate (Leucine)

Describe the etiology of Maple Syrup urine disease.

Individuals with this disease would not be able to metabolize what?

Maple syrup urine disease is a deficiency of the enzyme Acyl CoA Dehydrogenase. It is a congenital neurological disorder which can be lethal within two years of life if not diagnosed.

the BCAAs (Valine, Isoleucine, Leucine)