Biochemistry Flashcards
What is the primary focus of nucleotide metabolism?
Biosynthesis and degradation of purine and pyrimidine nucleotides
Emphasis on key regulated steps
What are the purine salvage pathways?
Pathways that synthesize purine nucleotides from preformed purines
Clinical correlation is significant
Which diseases are related to nucleotide metabolism?
Examples include Lesch-Nyhan Syndrome and Severe Combined Immunodeficiency Disease (SCID)
Symptoms and treatments vary
What is the importance of nucleotides?
- DNA and RNA biosynthesis
- Coenzymes for biosynthesis
- Energy currency (ATP, GTP)
- Activation of biosynthetic intermediates
- Second messengers
- Allosteric regulators of metabolism
What is the committed or rate-limiting reaction in purine biosynthesis?
Formation of 5-phosphoribosylamine
Uses glutamine as the nitrogen donor
What enzyme catalyzes the synthesis of Inosine monophosphate (IMP)?
Glutamine-PRPP amidotransferase
Inhibited by purine ribonucleotides
What are the major contributors to purine biosynthesis?
- Glutamine
- Glycine
- Aspartate
- Ribose 5-phosphate
- CO2
- Folate
- ATP
- GTP
True or False: IMP is the key intermediate for both AMP and GMP.
True
What inhibitors affect purine biosynthesis?
- Sulfonamide
- Methotrexate
What is the role of Mycophenolic acid?
Immunosuppressant
Used in various clinical settings
What enzymes are involved in the negative feedback regulation of purine biosynthesis?
- PRPP synthetase
- Glutamine phosphoribosyl amidotransferase
- Adenosuccinate synthetase
- IMP dehydrogenase
What is the end product of purine degradation?
Uric acid
Excreted primarily in urine
Fill in the blank: Hyperuricemia is defined as a serum urate concentration exceeding _______.
6.5 mg/dL
What are the symptoms associated with gout?
Formation and deposition of urate crystals leading to inflammation
Symptoms include pain and swelling
What is the treatment for gout that reduces uric acid production?
- Xanthine oxidase inhibitors (e.g., Allopurinol)
- Anti-inflammatory drugs (e.g., NSAIDs)
What dietary restrictions are recommended for managing gout?
- Avoid foods rich in purines
- Low protein diet
- Avoid alcohol and caffeine
What is the role of Carbamoyl phosphate in pyrimidine biosynthesis?
Source for building pyrimidine rings
Made from glutamine, CO2, and ATP
What is the rate-limiting step in pyrimidine biosynthesis?
Carbamoyl phosphate synthetase II (CPSII)
Inhibited by UTP
What is the key intermediate in pyrimidine biosynthesis?
UMP (uridine monophosphate)
What is the function of Thymidylate synthase?
Methylates dUMP to form dTMP
Requires tetrahydrofolate as a methyl donor
True or False: Orotic aciduria is associated with a defect in UMP synthase.
True
What is the clinical significance of adenosine deaminase deficiency?
Accumulation of adenosine and deoxyadenosine leading to SCID
Both B and T cells are affected
What is the product of the reaction dUDP → ?
dUMP + Pi
Which compound is required as the methyl donor in the synthesis of dUMP?
tetrahydrofolate (N5,N10-methylene tetrahydrofolate)
What enzyme is referred to as ribonucleotide reductase?
RR
What role does thymidylate synthase serve in the conversion of dUMP?
Methylates the base on dUMP using THF as the one carbon donor
What is THF oxidized to during the methylation process?
DHF
What enzyme converts DHF back to THF?
dihydrofolate reductase
What cofactor is used by dihydrofolate reductase to convert DHF to THF?
NADPH
Which amino acid donates one carbon in the synthesis process?
Serine
Is the synthesis of thymidylate regulated?
Not regulated
What is the function of dihydrofolate reductase in cancer therapy?
Reduces DHF to THF and is inhibited by methotrexate
What do many anti-cancer drugs target in relation to dTMP synthesis?
Thymidylate synthase or DHFR
What is the primary role of ribonucleotide reductase (RNR)?
Reduces NTPs to dNTPs
What effect does dATP have on RNR?
Inhibits RNR
What is Hydroxyurea (HU) used for in cancer treatment?
RNR inhibitor
What condition is Hydroxyurea also used to treat?
Sickle cell anemia
What pathway involves pyrimidine salvage reactions?
Pentose Phosphate Pathway
What enzyme converts pyrimidine bases to nucleosides?
Pyrimidine nucleoside phosphorylase
What enzyme forms nucleotides from nucleosides?
Nucleoside kinase
What is the function of thymidine kinase (TK)?
Salvage enzyme elevated in rapidly growing tissues
What inhibits thymidine kinase?
dTTP
What are the products of pyrimidine degradation?
- CO2
- NH4+
- β-alanine
- β-aminoisobutyric acid
What is the clinical significance of pyrimidine metabolism?
No clinical problems associated
What are key concepts in purine and pyrimidine biosynthesis?
- Contributing molecules
- Committed step
- Rate-limiting step
- Regulations
- Clinical relevance
What are some clinical correlations related to purine metabolism?
- Lesch-Nyhan Syndrome
- Adenosine deaminase deficiency
- Hyperuricemia
- Gout
- Orotic aciduria
What is a common symptom of gout?
Throbbing pain in the right great toe
What is a non-pharmacological treatment for acute gout?
Topical ice and rest of inflamed joint
What NSAID is commonly used to treat inflammation in gout?
Naproxen
What is the chronic treatment for gout after inflammation subsides?
- Xanthine oxidase inhibitors (allopurinol/febuxostat)
- Uricosuric drugs (Probenecid)
What factors might lead to precipitation of urate crystals in joints?
Diet and illness
Why might cancer patients treated with chemotherapy develop gout?
Increased cell turnover leads to urate production
Why is a patient with Lesch-Nyhan syndrome predisposed to gout?
Defective purine metabolism leads to increased urate production
How does allopurinol help alleviate gout symptoms?
Inhibits xanthine oxidase, reducing urate levels
What are the nonessential amino acids synthesized in the body?
11 nonessential amino acids
These include alanine (A), aspartate (E), asparagine (N), glutamate (D), glutamine (Q), proline (P), serine (S), and tyrosine (Y) among others.
Which vitamins are involved in the transfer of one carbon units?
Folic acid, cobalamin (Vitamin B12), S-adenosylmethionine (SAM)
These vitamins play key roles in various metabolic reactions involving one-carbon transfers.
What is the role of tyrosine in catecholamine synthesis?
Tyrosine is a precursor for catecholamines
Catecholamines include dopamine, norepinephrine, and epinephrine.
What amino acid is a precursor for GABA synthesis?
Glutamate
GABA (gamma-aminobutyric acid) is synthesized from glutamate through decarboxylation.
What is the coenzyme derived from Vitamin B6 used in transamination reactions?
Pyridoxal Phosphate (PLP)
PLP is essential for the function of aminotransferases.
What is the primary function of glutamine synthetase?
To incorporate ammonia into glutamate to form glutamine
This reaction is crucial for detoxifying ammonia in the body.
Fill in the blank: Glycine is synthesized from serine by enzymatic removal of the serine _______.
CH2-OH
What is the consequence of a deficiency in Vitamin B12?
Megaloblastic anemia and neurological damage
B12 deficiency can also lead to elevated homocysteine levels, increasing cardiovascular risk.
True or False: Sulfa drugs kill bacteria by blocking the synthesis of folate.
True
Humans do not synthesize folate, hence are not affected by sulfa drugs.
What is the role of S-adenosylmethionine (SAM) in metabolism?
Methylation reactions
SAM acts as a methyl donor in various biochemical reactions.
What is the main reaction involving Vitamin B12 in the body?
Synthesis of methionine from homocysteine
This reaction is crucial for maintaining normal homocysteine levels.
What is the significance of tetrahydrofolate (THF) in metabolism?
It is a key carrier of one-carbon units
THF is involved in the synthesis of nucleotides and amino acids.
Identify the amino acid precursor for serotonin synthesis.
Tryptophan
Serotonin is synthesized from tryptophan through a series of enzymatic reactions.
Fill in the blank: A deficiency in folate can lead to _______ defects in developing fetuses.
neural tube
What is the effect of increased levels of homocysteine in the blood?
Associated with cardiovascular disease
Elevated homocysteine levels can result from deficiencies in B12, folate, or B6.
What is the role of tyrosinase in albinism?
Tyrosinase is required for melanin synthesis
Deficiency or malfunction of tyrosinase leads to reduced melanin production, causing albinism.
What is the consequence of an autoimmune reaction leading to destruction of intrinsic factor?
Pernicious anemia
This condition results in the inability to absorb Vitamin B12, leading to severe deficiencies.
What are three main reactions for incorporating free ammonia into non-toxic organic compounds?
- Formation of carbamoyl phosphate (CPS-I, Urea cycle)
- Glutamine synthetase reaction
- Glutamate dehydrogenase reaction
What is the primary precursor for the synthesis of creatine?
Glycine and arginine
Creatine is synthesized in the kidneys and liver before being transported to muscles.
What is the significance of the methyl trap hypothesis?
It explains the functional folate deficiency due to B12 deficiency
This results in the accumulation of a dead-end folate derivative.
What role does methotrexate play in relation to folate?
Blocks the activation of dietary folate by inhibition of the NADPH reduction to its coenzyme form: FH4
This inhibition can affect nucleotide synthesis and is used in cancer treatment.
What is the relationship between Vitamin B12 and folate in one-carbon metabolism?
B12 is necessary for the conversion of homocysteine to methionine
This links the metabolism of folate and B12 in one-carbon transfers.
What is the role of a DOPA decarboxylase inhibitor?
It prevents decarboxylation before DOPA enters the brain
This is important for treating conditions like Parkinson’s disease.
What are the precursors of catecholamines?
Phenylalanine
Catecholamines include Dopamine, Norepinephrine, and Epinephrine.
What is the key reaction for the biosynthesis of catecholamines?
PLP-dependent decarboxylation
What are the three enzymes involved in the degradation of catecholamines?
- COMT (Catechol-O-Methyl Transferase)
- MAO (MonoAmine Oxidase)
- ALDH (aldehyde dehydrogenase)
How does COMT deactivate catecholamines?
By methylation on phenolic-OH via SAM
What role do MAO inhibitors play in treating Parkinson’s disease?
They slow the oxidation of dopamine.
What are the excreted products of catecholamine degradation?
Vanillyl Mandelic Acid (VMA) and related metabolites
What are other uses of Tyrosine?
- Thyroid hormones
- Melanin
What is the significance of creatine phosphate?
It is a high energy compound in muscle.
What is the relationship between creatinine and muscle mass?
Creatinine is used to estimate muscle mass.
What is a clinical indicator of kidney function?
Blood creatinine levels
What is the consequence of Vitamin B12 deficiency?
Irreversible neurological damage
What condition is associated with a lack of intrinsic factor?
Pernicious Anemia
What is the result of B12 deficiency on folate?
B12 deficiency causes folate to become tied up in a useless form.
What is the Methyl Trap hypothesis?
When B12 is deficient, folate is trapped in the form of N-5-Methyl FH4.
What are the consequences of elevated homocysteine levels?
Increased risk of cardiovascular mortality
What are the two ways to reduce homocysteine levels?
- React with Serine to synthesize Cysteine
- Resynthesize Methionine using B12 and folate
What are the symptoms of megaloblastic anemia?
Enlarged red blood cells that are low in hemoglobin
What is a clinical correlation associated with high methionine and homocysteine levels?
Possible mutation in Cystathionine Synthetase (CS) or Cystathionine Lyase (CL)
What treatment options are suggested for elevated methionine and homocysteine levels?
- Restrict methionine in the diet
- Supply cysteine and choline
- Supplement vitamins B6, folate, and B12
What indicates elevated levels of vanillylmandelic acid (VMA) in the urine?
Increased catecholamine production
What is the role of Pyridoxal Phosphate (PLP) in amino acid metabolism?
It is involved in the transfer of amino groups.
What is Methotrexate used for?
It is used in cancer chemotherapy to block folate activation.
PLP is a coenzyme derived from this vitamin required for this enzyme
derived of Vit. B6
required for activation of ALT & AST
What are the substrates for ALT
Glutamate & pyruvate
what are the substrates for AST
oxaloacetate & glutamate
how are digested proteins absorbed into the liver
via the portal vein
glutamine is synthesized from glutamate. T or F.
True
how is glutamate modified to be used for the synthesis of other AAs?
addition of an ammonia group
What is the precursor for glutamate synthesis
alpha-ketoglutarate
The conversion of serine to glycine is a substitution rxn. in which serine’s R-group is exchanged for what biomolecule
tetrahydrofolate
what end product of serine conversion to glycine can be used for purine ring synthesis and the pyrimidine: thymidine
5,10-methylene-FH4
The free R group from serine is used to synthesis what AA
cysteine
what are the cofactors for cystine synthesis
SAM; Vit. B6 & 12
the sulfur group in cystine is derived from what essential AA
methionine
T or F: Vit. B12 contributes to the carbon of cystine while Vit. B6 contributes to the sulfur group of cystine
False
It is the other way around
what is the difference b/t cysteine & homocysteine
homocysteine does not contain the carbon donor from serine
describe how the feedback inhibition of cystine synthesis works
cysteine inhibits cystathionine synthase conversation of homocysteine to cystathionine
T or F: both the cystathionine synthase & lyase require PLP
True
the homocysteine carbon skeleton is released as what
alpha-ketobutyrate
what enzyme converts phenylalanine to tyrosine
phenylalanine hydroxylase
T or F: Trimethoprim is a variant of methotrexate more specific for bacterial reducase enzymes?
True
Vit. B12 is involved in what 2 biochemical processes
synthesis of methionine from homcysteine
production of succinyl CoA in odd and branched FA synthesis
synthesis of catecholamines
What metabolites are used to measure adrenal production of catecholamines
VMA
what is the substrate for initiation of catecholamine synthesis
phenylalanine
what AAs act as substrates for the synthesis of creatine
Arginine & glycine
What is the degraded form of creatine called
creatinine
T or F: phenylalanine must first be converted to tyrosine for synthesis of catecholamines
True
T or F: Vit. B6 & Vit. B12 can be used to resynthesize methionine b/c this rxn. is reversible
False
resynthesis of methionine requires Vit. B12 and folate
Explain how a deficiency of cobalamin also causes folate deficiency
In the absence of B12, folate cannot be recycled back into its active form, THF. this is referred to as the Methyl Trap
what is the ultimate fate of the bast majority of dietary purines & pyrimidines
conversion into uric acid to be excreted in urine
what is the main site in the body for nucleotide synthesis
liver
what is the difference b/t a nucleotide & a nucleoside
they are identical in almost every way except nucleosides lack the phosphate group
PRPP is derived from what PPP metabolite?
ribose-5-P
IMP can be converted to either GMP or AMP. describe the process for each
AMP:
aspartate added to IMP
GMP:
IMP converted to XMP; ammonia generated from glutamate-glutamine conversion attaches to IMP to make GMP
what AA is the primary source of ammonia for pyrimidine synthesis
glutamine
Describe the salvage pathway for purine synthesis
PRPP - adenosine
PRPP - guanine
T or F: UTP is produced from CTP
False
it is the other way around: UMP is a very important key intermediate for the synthesis of other pyrimidines
what are key urea cycle intermediates that are used as substrates for the synthesis of pyrimidines
orotate
what coenzyme is required for the conversion of UMP to dTMP
folate
what happens to folate when used for thymidine synthesis
THF is oxidized to DHF and then converted back to THF by DHFR and NADPH
Describe the salvage pathway for pyrimidine synthesis
PRPP plus a free base
