Conversion Of Amino Acids To Specialized Products and Purine/Pyrimidine Nucleotide Metabolism Flashcards
Creatine
. Reserve of high-energy phosphate in muscle that can be rapidly mobilized to regenerate ATP from ADP during muscle contraction
. ADP + Cr-P ATP + Cr via creatine kinase
Creatine synthesis
. In kidney
. Guanidine group of Arg transferred to Gly forming guanidinoacetate (GAA)
. GAA brought to liver and methylated by S-adenosylmethionine to form creatine
. Brough to muscle
T/F small portion of total creatine is irreversibly cyclized to creatinine and excreted in urine
T
Urinary creatinine is estimate of ___
Muscle mass
Serum creatinine is measure of ____
Kidney function
S-adenosylmethionine
. Used in over 35 rxns as methyl donor
. Contains activated methyl group formed via condensation w/ ATP
. This can be used in methylation rxns catalyzed by methyltransferase enzymes
After methylation rxns. S-adenosylmethionine is converted to ___
Adenosylhomocysteine
How is methionine regenerated from homocysteine?
. Betaine from choline or 5-methyltetrahydrofolate as methyl donor (Vit. B12 dependent)
. Homocysteine then used to make cysteine or is excreted in urine
Nitric oxide and physiological mechanism
. Gas molecule
. Vasodilator, neurotransmission, immune function/inflammation
. Generated from guanidine nitrogen of Arg through nitric oxide synthase
. Formed in endothelial cells
. Diffuses into smooth muscles and binds to/stimulated gaunylyl cyclase
. Inc. cGMP and smooth muscle relaxation
NO isozymes
. Constitutive (cNOS)
. Inducible (iNOS)
. Neuronal (nNOS) in brains and nervous tissue as signaling molecule
Thyroid hormone synthesis
. Thyroxine (T4) and triiodothyronine (T3)
. Iodination and coupling of Tyr residues on prohormone thyrogobulin
. T4/3 proteolytically released from thyroglobulin is response to TSH
T3/4 functions
. Regulate metabolism
. Mediate thermogenesis
Iodine deficiency
Lack of iodine causes hypothyroidism and goiter
Melanin
. Formed via Tyr via enzyme tyrosinase as shown below
. Synthesized in skin
.
Albinism
. Results from deficiency of tyrosinase in melanocytes
Catecholamine neurotransmitters
. From Tyr
. Sequentially L-dopa, dopamine, NE, and epinephrine
. NE and E are regulators of carb, protein, and lipid metabolism
DOPA-decarboxylase is ____ dependent
B6
Conversion of dopamine to NE rxn
. Catalyzed by copper-containing enzyme dopamine beta-hydroxylase
. Dependent on Vit. C (ascorbate)
Parkinson’s disease and treatment mechanism
. Dopamine neuron degeneration
. Uses L-dopa and DOP carboxylase inhibitor doesn’t cross BB to control symptoms
. L-dopa taken up by neurons and converted to dopamine by DOPA-decarboxylase
. Carbidopa minimizes decarboxylation of L-dopa in liver and other tissues outside of brain
. MAO and COMT inhibitors help too
Catecholamines are inactivated by ____
. Oxidative deamination
. O-methylation
. Also inactivate serotonin
MAO inhibitors
. Antidepressant drugs that prolong NE and serotonin
Serotonin formation
. 2-step rxn involving hydroxylation (BH4 dependent) and decarboxylation (B6 dependent) of Trp
Melatonin formation
. In pineal gland
. Serotonin converted
. Involved in entrainment of circadian rhythm
Gamma-aminobutyric acid (GABA)
. Glu synthesized from direct amidation w/ ammonia or transamination of alpha-ketoglutarate
. Glu decarboxylated by Glu decarboxylase (GAD) to form GABA
GABA shunt
. GABA stored in vesicles
. Released into synapse
. Acts on GABA receptors for inhibitory action potential
. Uptakes through GABA transporters around neurons
. Metabolized through transamination into succinic semialdehyde catalyzed by GABA-transaminase
Acetylcholine formation
. Formed by Ser by sequential decarboxylation, methylation, and acetylation
Histamine
. Vasodilator
. Formed by decarboxylation of His
. Secreted from mast cells in response to inflammatory and allergic rxns
Antihistamine drugs
. Modulators of allergic responses from inc. histamine secretion
Activated precursors of DNA and RNA
. nucleotides
Activated intermediates in biosynthesis
. UDP-glucose in glycogen synthesis
. Adenosyl methionine in methyl-transfers
. CDP-alcohol in membrane phospholipid biosynthesis
Nucleotides in cellular communication and regulation
.cAMP as second messenger
. GTP/GDP
. ADP in blood clotting
Foods high in nucleotides
. Organ meats . Anchovies . Yeast . Sardines . Dark beer
T/F dietary nucleotides are incorporated into DNA
F, they’re broken into Uric acid
Dietary nucleotides in GI tract
. Broken down by stomach acid and enzymes (pancreatic phosphodiesterases, nucleases, and nucleotidases)
. Some used for ATP synthesis
. Most degraded/excreted, ribose or deoxyribose is metabolized
Location of nucleotide biosynthesis
Cytoplasm of all tissues
components of purine synthesis
. ATP
. amino acids Glu, Gly, Asp to provide nitrogen atoms and parts of carbon skeleton
. Folic acid (form is 10-formyl-tetrahydrofolate)
. Occurs in cytoplasm of all tissues
. Ring built bit by bit on ribose
Components of pyrimidine
. ATP . Aspartic acid, Gln . Folic acid . Make sUMP . UMP is modified to form pyrimidine nucleotides needed (CMP/TMP)
Nucleotide salvage of purines and pyramidines
. Recycling of free bases that become separated from sugar
. Several enzymes that attach an activated ribose to free base
Orotic aciduria
. Genetic disease of pyrimidine biosynthesis
. Autosomal recessive
. Low protein activity in pyrimidine synthesis
. Impaired ability to make cytosine, thymine, and uracil
. Accumulate orotic acid/orotate
. Symptoms: failure to thrive, macrocytic megaloblastic anemia, orotic aciduria
. Treatment: exogenous uridine (precursor to all 3 bases)
Latch-Nyhan syndrome
. Genetic defect in purine salvage
. Affected enzyme: hypoxanthine-guanine phosphoribosyl transferase (HGPRT)
. Catalyzes hypoxanthine + PRPP to IMP + pyrophosphate and guanine + PRPP to GMP and pyrophosphate
. X-linked, rare
. Symptoms: mental impairment, involuntary movements, self-mutilation, high uric acid levels, gout later in life
Folic acid
. Water-soluble vit.
. Carries 1C units in enzymatic rxns
. Essential for rapid growth
. Structure: Pterin ring (p-aminobenzoate) and polyglutamate tail
. Named for oxidized form in pills, reduced derivatives are biologically active
What foods are supplemented w/ folic acid
Breads and cereals
Anti-folate chemotherapy
. Kills all cells, not just cancer
. Rapidly dividing cells killed first (gastric mucosa, hair follicle cells)
. Hair loss and vomiting side effects
Fluorouracil drug
.inhibits thymidylate synthase by binding irreversibly
. Cells die by lacking thymidylate for DNA synthesis
.nontoxic substance that converts into toxic form in body (FdUMP)
Methotrexate
. Folate analog for chemo
. Inhibits dihydrofolate reductase (DHFR)that furans H2folate + NADPH into H4folate
. Starves rapidly growing cell for folate
Hydroxyurea
. Inhibits ribonucleotide reductase
. Enzyme makes all deoxyribonucleotides needed by cell
. Used for cancer and HIV treatment and sickle cell
Ribonucleotide reductase rxn
. Nucleotide diphosphate + NADPH -> deoxy-nucleotide disphosphate
. Uses CDP, UDP, ADP, and GDP
.dATP powerful inhibitor
. Need NADPH
Sulfa drugs
. Analogs of p-aminobenzoic acid
. Acts as substrate for folate biosynthetic enzyme incorporated into folate in bacteria
. Inhibits next step, bacteria starved for folate, dies
. Works bc bacteria can’t transport folate
Purine and pyrimidine catabolism
. Break down pyrimidine ring into energy-yielding metabolites but not major energy pathway
. Can’t break down purine rings for ATP, they are converted to uric acid and excreted
. Pyrimidines broken down to acetyl CoA and succinyl CoA
Severe combined immunodeficiency disease (SCID)
. Autosomal recessive disease in purine catabolism
. Adenosine deaminase (ADA) deficiency
. Don’t generate function B/T cells so people die by age 2
. Diagnosed by recurring infections, confirmed by measurement in blood
. Deoxyadenosine accumulates in blood and converted to dATP, ribonucleotide reductase inhibited, cells can’t divide
SCID treatment
. Children isolated
. Bone marrow transplant w/ HLA identical donor
. Gene therapy potential
Gout
. Chronic hyperuricemia w/ acute attacks of inflammatory arthritis from urate crystals in joints
. Affects 4% pop. And 50% develop arthritis in big toe, feet joints, or lower extremities
. Can have nephropathy from crystal damage to kidneys
. Diagnosed during 1st attack of inflammatory arthritis and confirmed by crystals in tissue sample
High serum urate result of _____
. Too much uric acid production (excessive cellular breakdown)
. Too little uric acid excretion (excessive renal retention)
Gout factors
. Age (old)
. Sex (more common in men, inc. in women after menopause)
. Weight (obese, high meat and alcohol)
. Drug use (drugs that inc. acidity of tissue, act as diuretic and dec. liquid uric acid is dissolved in, uric acid excretion inhibited)
High serum urate lab levels
. Males over 7.0 (onset 30-50)
. Females over 6.0 (onset 50-70)
Why is gout onset later in women?
Premenopausal estrogen levels cause inc. uric acid excretion from dec. urate reabsorption in kidney
How urate crystals damage tissue
. Cells take up crystals by phagocytosis
. Cells rupture
. Lysosomal enzymes released into tissue to induce inflammatory response
End product of purine catabolism
Uric acid
In neutral pH, uric acid forms crystals of ___
Sodium urate
In acidic pH, uric acid forms crystals of ___
. Uric acid
. Common in urine
Alllopurinol
. Gout treatment for preventative for attacks
. Analog of xanthine and inhibits xanthine oxidase
. Converts xanthine oxidase to alloxanthine that inhibits enzyme even more
. Causes production of soluble compounds that are easier to excrete
Febuxostat
. Prevents acute gout attacks
. Xanthine oxidase inhibitor
. Works better than allopurinol due to less drug interactions but is more expensive
Probenecid
. Preventative treatment for gout
. Facilitates excretion of uric acid by blocking reabsorption in kidney
Colchicine
. Used for acute gout
. Prevents and blocks inflammatory response that causes pain
. Binds to microtubules and prevents cell from phagocytosis crystals of uric acid
Indocin
. Used for acute gout attacks
. Non-steroidal anti-inflammatory
Elitek (rasburicase)
. Used to prevent gout int hose w/ tumor lysis syndrome
. People develop high uricemia from chemotherapy
. Genetically engineered form of enzyme uricase that converts uric acid to allantoin that is water soluble
PRPP synthetase
. Used in purine biosynthesis
. Not committing step bc it is used in pyrimidine synthesis too)
. PRPP inhibited by purine nucleotide diphosphates and purine nucleotide triphosphates
. Activated by phosphate
PRPP aminotransferase
. Regulatory step . Driven by hydrolysis of pyrophosphate . Inhibited by AMP, GMP, and IMP . Any small inc. in substrate will result in proportional inc. in enzyme activity . Sensitive to PRPP
Mycophenolic acid
. Inhibitor of IMP dehydrogenase
. Impairs growth of rapidly dividing Band T cells
. Prevents graft rejection in transplant patients
Synthesis of GMP requires ___
ATP
Synthesis of ATP requires ____
GTP
Synthesis of GMP inhibits ___
Conversion of IMP to XMP
. First step unique to GMP synthesis
AMP inhibits conversion of __
. IMP to adenylsuccinate
. First stepunique to AMP synthesis
Carbamoyl phosphate synthetase II
. Regulatory step in pyrimidine synthesis
. Inhibited by UTP
. Activated by ATP and PRPP
.
Carbamoyl phosphate synthetase I cycle in, compartment tissue, amino donor, and anabolic or catabolic?
. Urea cycle
. Catabolic
. Mitochondria in liver
. Ammonia as donor
Carbamoyl phosphate synthetase II cycle in, anabolic or catabolic, compartment tissue,, and amino donor
. Pyrimidine biosynthesis
. Anabolic
. Cytosol and all tissue
. Gln is donor
Cytidylate synthetase
. Changes UTP to CTP
. Goes from UMP -> UDP -> UTP is different enzyme
Ribonucleotide reductase
. UDP -> dUDP . Broad substrate specificity . Makes all deoxyribonucleotides needed by cell . Needed NADPH . DATP powerful inhibitor . Inhibited by hydroxyurea
Thymidylate synthase
.dUMP -> dTMP
. Important in chemotherapy
Purine salvage pathway
. HGPRT used to make IMP or GMP and pyrophosphate from PRPP and hypoxanthine (IMP) or guanine (GMP)
. APRT forms AMP and pyrophosphate from adenine and PRPP
Pyrimidine salvage pathway
. Pyrimidine phosphoribosyltransferase used
. Makes pyrimidine nucleotide from pyrimidine base and PRPP
Purine nucleoside phosphorylase deficiency
. Loss of T cell function . Normal B cells . Symptoms: recurrent infections in infancy and childhood . Rare recessive mutation . Affects purine catabolism
