Section VI (Chapters 36-39) Flashcards
Fate of amino acid nitrogen in liver (fasting)
AA nitrogen (from alanine or others) converted in liver => urea (excreted in urine by kidney)
Fate of amino acid nitrogen in kidneys (fasting)
AA nitrogen (glutamine) converted to alanine removing NH3 in kidney => ammonia excreted in urine and alanine transported to liver
What is the form of nitrogen excreted by the kidney?
Kidney secrete NH4+ in urine to form salts with metabolic acids, facilitating their excretion
What is the role of ammonia in urine?
Ammonia (NH3) neutralizes the acidity of the urine
What are the biochemical methods for removing nitrogen from amino acids?
Transamination: move amino-group from AA to α-keto acid (α-KG) to form another AA (Glu); enzyme used is pyridoxal phosphate
Deamination: Glu, Asp, Ser, Thr & His can be dehydrated & release NH4+
Which 2 amino acids CANNOT undergo transamination?
lysine and threonine
What is the role of pyridoxal phosphate in amino acid metabolism?
PLP is a cofactor for transamination, and assists with deamination of serine and threonine
What are the major symptoms of PLP deficiency?
PLP/VitB6 deficiency affects AA metabolism, heme synthesis, glycogen phosphorylase & NT synthesis => dementia, dermatitis, anemia, weakness & convulsion
What is the reaction that produce ammonia in the body?
Deamination & deamidation (Gln/Asn) => NH4+
What is the fate of urea that enters the gut?
Becomes NH4+, then transported to muscle or brain for PNC
How does aminotransferases (transaminases) coordinately funnel amino groups into urea?
α-KG and aspartate and transaminase=> glutamate (NH4+)
How does glutaminase coordinately funnel amino groups into urea?
Glutaminase and glutamine => glutamate (NH4+)
How does glutamate dehydrogenase coordinately funnel amino groups into urea?
Glutamate and glutamate dehydrogenase (with NAD+ or NADP+) => a- KG and NH4+
What is the glucose alanine cycle?
Glucose-alanine cycle refer to the moving of carbon/nitrogen between liver/muscle;
muscles glycolysis makes pyruvate which is converted to Ala by transamination, then sent to liver => broken down to urea + glucose => back to muscle
How does glutamine & alanine help get rid the body of toxic ammonia?
In tissues, α-KG => Glu by glutamate dehydrogenase and picking up NH4 with NADPH oxidation=> Gln by glutamine synthetase and picking up NH4+ with ATP use, then sent to liver => breakdown to Glu + NH4+ by glutaminase => α-KG + NH4+ by glutamate dehydrogenase => urea
What is nitrogen balance?
Nitrogen balance: N ingested= N excreted; (+) = over-ingestion vs (-) = over-excrete
Synthesis of urea by the urea cycle, identifying the sources of the amino groups of urea
N source: NH4+ & Asp
1. NH4+, CO2, H2O, HCO3 use CPSI=> carbamoyl-P
2. CP + ornithine with orn. Transcarbamolyase => citrulline
3. Cirtrullene exported from cell mt, + aspartate, ATP with arginonsuccinate synthetase=> arginosuccinate
4. Arginosuccinate + lyase=> fumarate & arginine
5. Arginine with arginase => Urea & ornithine (back into mitochondria to contribute to 2)
What is the role NAG/N-acetylglutamate in the urea cycle?
- allosterically activates CPSI
- synthesized from acetyl CoA and glutamate, stimulated by arginine
- results in induction/repression of synthesis of urea cycle enzymes
What are the consequences of NH3 toxicity?
↑NH3 is toxic to nervous system
Glutamine levels rise, a-KG no longer generated so no longer able to fix free ammonia
Brain swelling due to osmotic imbalance from high ammonia and glutamine
What is the treatment for Hyperammonemia & urea cycle disorders? What if the enzyme defect comes after the synthesis of argininosuccinate?
Low protein diet
Arginine supplementation which helps form arginosuccinate causing ↑ornithine by arginase & enhance urea excretion by arginosuccinate
What is the impact of benzoic acid & phenylbutyrate on hyperammonemia & urea cycle disorders?
Benzoic acid or phenylbutyrate supplementation causes conjugation of Gly to form hippuric=> excreted; Phenylbutrate binds Gln => excreted
Both tx removed AAs from body and force body to use nitrogen to synthesize more Gly/Gln
What are the cofactors needed for amino acid metabolism?
PLP/vitB: transamination, deamination, decarboxylation, racemization, β/γ-elimination
FH4/Folate: transfer 1-C-groups;
BH4: ring hydroxylation => Tyr/NT
What are non-essential amino acids?
Asp, Asn, Gly, Ser, Ala, Cys, Tyr, Glu, Gln, Pro & Arg
What are essential amino acids?
Phe, His, Iso, Lys, Leu, Met, Thr, Val, Trp
What does glucogenic amino acids mean?
Can convert to precursor of glucose
What does ketogenic amino acids mean?
Can convert to acetyl-CoA or acetoacetate
What amino acids are ketogeneic?
Leu, Lys (Leucine & lysine)
What are the nonessential amino acids made from or metabolized back to glycolytic intermediates?
Ser, Ala, Cys, Thr, Gly & Trp
What are the nonessential amino acids can be made from/metabolized to TCA intermediates?
Asp, Asn, Glu, Gln, Pro, Arg, His, Met, Thr, Val, Iso, Phe & Tyr
Why is arginine is an essential amino acid in a newborn, not an adult?
Urea-cycle synthesis of Arg (protein synthesis) cannot support growth in newborn, need more than what is synthesized
What is cystathioninuria?
Benign presence of cystathionine in urine due to cystathionase deficiency
What is cystinuria?
Inability to transport cys/lys/arg/ornithine into intestine => renal stones
What is homocystinuria?
Disorders in the metabolism of homocysteine; inherited as autosomal recessive
high plasma/urinary levels of homocysteine and methionine and low levels of cysteine
What is the most common of enzyme defect in homocystinuria?
Defect in cystathionine β-synthase
How does homocystinuria present?
Homozygotes exhibit ectopia lentis (displacement of the lens of the eye), skeletal abnormalities, premature arterial disease, osteoporosis, and intellectual disabilities
What treatment is for homocystinuria?
Includes restriction of methionine intake & vitamins B6, B12,& folate supplement
How will vitamin deficiences in folate, vitamin B12, or vitamin B6 can lead to homocystinuria?
Deficit FH4/VitB12 would inhibit homocysteine => methionine
Deficit PLP/VitB6 would inhibit homocysteine => cysteine
What is maple syrup urine disease?
Defect in α-keto acid DH => ↑ α-keto acids => intellectual/neurological disabilities, present in urine giving odor of maple syrup
Defect in BCAAs degradation = ↑BCAAs
What is the inborn error of PKU?
Phe => Tyr, requires phenylalanine hydroxylase, O2 and cofactor BH4-converts to dihydrobiopterin (deficiency in any of the enzyme paths can cause build up of amino)
What are the symptoms of PKU? What treatment?
sx: intellectual disability, delayed psychomotor skills, tremor, seizures, eczema & hyperactivity;
tx low Phe diet therapy
How is phenylalanine & tyrosine metabolism impacted in terms of inborn errors in metabolism?
Deficient enzymes in Tyr metabolism => tyrosinemia (I/liver failure, cabbage odor & death vs II/lesion of eye/skin & neuro issues) & alkaptonuria (dark urine & joint pain)
How is the metabolism of tyrosine impact Parkinson’s disease?
Defective dopamine synthesis in substantia nigra correlates with Parkinson’s Disease.
Tx with DOPA (DihydrOxyPhenylAlanine), which crosses the BBB, and a peripheral DOPA decarboxylase inhibitor, which doesn’t cross BBB. Prevents decarboxylation before DOPA enter brain
What is the role of folate in metabolic reactions?
FH4 = 1-carbon carrier with different oxidation states => biosynthesis
What are the recipients of one-carbon units?
1-carbon unit +: dUMP => dTMP; Ser => Gly; purine precursor => purine ring (FH4 required for cell division), methyl to vitB12
What is the structure of tetrahydrofolate?
FH4 has 3 components: pteridine ring, para-aminobenzoic acid & polyglutamate tail; 1-carbon group binds N5/10
Different folates: # of glutamate residues/pteridine ring oxidation
What is the use & mechanism of action of methotrexate?
Methotrexate = FH4 analog that inhibit dihydrofolate reductase (DHFR) = ↓FH4 = anticancer because DNA synthesis cannot occur
What is the structure of vitamin B12?
Also known as cobalamin
Corrin ring (similar to porphyrin ring in heme) with Co at center
Two of four pyrrole rings jointed directly rather than methylene bridge unlike heme
Co reacts with methyl groups forming methylcobalamin
What is the dietary absorption of vitamin B12 and the effects of impaired digestion on B12 absorption?
Ingest B12 is either bound to dietary proteins or found free
Free bind to R binders secreted by salivary glands and gastric mucosa
If bound, must be released by digestive proteases
Free then binds to intrinsic factors which internalizes
Malabsorption due to inheritied defect of intrinsic factor production, resection of stomach or ileum, intrinsic factor decline with age, or pancreatic insufficiency causing prevention of protein complex degredation
What is the etiology, clinical manifestation and treatment of pernicious anemia?
Inherited/iatrogenic deficiency in intrinsic factor: malabsorption of B12 because it cannot be absorbed; tx with B12 injection or high oral dosage
What reactions involve tetrahydrofolate or B12?
FH4 is involved in the synthesis of Gly from Ser, dTMP/DNA, purine bases/DNA & RNA & transfer of methyl to B12
B12 is in 2 rxns: Homocysteine => Met; methylmalonyl-CoA => succinyl-CoA
What is the pathway for the synthesis of methionine and S-adenosylmethionine(SAM), identifying the important roles of folic acid (FH4) and B12?
B12 transfer methyl-group from FH4 to homocysteine => Met; Met + ATP => SAM
What is the methyl trap hypothesis & how folate/vit B12 deficiencies => hyperhomocysteinemia?
Methyl-trap hypothesis: B12 deficiency causes ↑methyl-FH4; ↓B12/FH4, reduces conversion of homocysteine to methionine resulting in ↑homocysteine
What is the connection between folic acid deficiency & neural tube defects?
Folate deficiency = inhibit/alter DNA synthesis => increase risk of neural tube defect
How does deficiency of vitamin B12 or folic acid leads to megaloblastic anemia
Deficient FH4/B12 resulting in fragmentation of DNA and blockage of normal DNA replication == clumping and abnormally large cells, and inability of blood cell precursors to synthesize DNA and divide, releasing only partial cells
What are uses & functions of nucleotides?
DNA/RNA, coenzyme (NAD+/FAD/CoA), energy (ATP), biosynthesis & regulation
Where does de novo synthesis of purines occur?
Liver & brain
What is the mode of transport around the body?
De novo synthesis using amino acids as precursors
RBC transport nitrogenous bases & nucleosides
What is the role of PRPP in nucleotide biosynthesis?
ATP + ribose-5-P (from PPP) uses enzyme phosphoribosyl 1 pyrophosphate synthase (PRPP synthase) => PRPP which is an activated ribose moiety for biosynthesis
What are the precursors and intermediates of de novo purine?
Purine ring: attached to ribose right away
Ribose-5-P +ATP => PRPP
+ Gln
+ Gly + (2x) N10-formyl-FH4 + Gln+ CO2 + Asp => inosine monophosphate (IMP)
AMP
Aspartate added to form adnylosuccinate (energy donated from GTP)
Fumarate released by adenylosuccinate lyase
GMP
Hypoxanthine base oxidized by IMP dehydrogenase to produce xanthine and nucleotide xanthosine monophosphate
Glutamine donates amide nitrogen to XMP
What are the precursors and intermediates of de novo pyrimidine synthesis?
Pyrimidine ring: base synthesized first, then ribose attached
Gln + CO2 + 2ATP => Carbamoyl phosphate
+ Asp => Orotate
+ PRPP => UMP (contains ribose)
What are the rate-limiting steps in nucleotide biosynthesis in purines?
Has 4 key enzymes: PRPP synthetase, amidophosphoribosyl-transferase, adenylosuccinate & IMP-DH
What are the rate-limiting steps in nucleotide biosynthesis in pyrimidines?
Pyrimidine synthesis is regulated at CPSII, inhibited by UTP and cAMP/PKA; activated by PRPP and MAPK
What is the role of folate in purine & pyrimidine synthesis?
Pyrimidine: add methyl to dUMP => dTMP
add C to purine ring
What is the synthesis of deoxynucleotides?
Ribonucleotide reductase reduce ribose to deoxyribose; require thioredoxin (provides H/e-) & NADPH (recycle thioredoxin)
What is the function of purine and pyrimidine salvage pathways?
Free/dietary bases & nucleotides can be used by most cells to make nucleotides
What is Lesch-Nyhan syndrome?
Defective hypoxanthine-guanine phosphoribosyltransferase (HGPRT); too much purine base not being converted to nucleotide = ↑uric acid/gout, development/intellectual disabilities
What are defects of PNP?
Deficiency in PNP = compromise T-cells, recurrent infection & neurologic complication
What are defects of ADA?
Deficiency in ADA = compromise BOTH T-cells & B-cells = no immune system
What is hereditary orotic aciduria?
Hereditary orotic aciduria => growth retardation; deficit in orotate phosphoribosyltransferase & orotidine 5’-P decarboxylase; cannot convert orotic acid to UMP
tx with uridine can bypass the metabolic block => CTP & dTMP
What are the symptoms of gout?
Degradation of purine could lead to gout = painful joints from uric acid build-up,
tx with allopurinol/ hypoxanthine analog, which inhibit xanthine oxidase; reduce uric acid synthesis
What is e the composition of the free amino acid pool in the blood and identify the primary factors affecting rate of turnover?
Free AA pool = dietary AA & turnover of proteins in the body,
determined by degradation from sk. muscle & liver
What are the souces of amino acids during fasting & after a protein meal?
Fasting = ↑ proteolysis (BCAAs) in sk. muscle vs. dietary AA from protein meal
What is the role of branched chain amino acids in skeletal muscle during fasting?
During a fast, sk. muscle oxidize BCAAs (valine, isoleucine, and leucine)
Carbon skeletons and nitrogen are converted to glutamine and alanine which will be converted to urea and glucose in liver
What is the role of glucagon & glucocorticoids on the liver’s handling of amino acids?
Glucagon & glucocorticoids cause liver to ↑ AA uptake => gluconeogenesis & ureagenesis
What is the role of glutamate in maintaining pH?
Glutamine in kidney neutralizes protons creating NH4+ and maintain body pH
What is the role of glucose-alanine cycle in relationship of skeletal muscle & the liver?
Sk. muscle oxidizes glucose to pyruvate, which can be converted to Ala and sent to liver to regenerate glucose for other tissues (brain, RBC, etc) & excrete nitrogen as urea
What is the major site of amino acid metabolism, and the major site for total protein in the body?
Liver, skeletal muscle
What is the role of amino acids in neurotransmitter synthesis?
40+ NT have nitrogen derived from precursor AA;
Glu/Gly act as NT
Catecholamines derived from Tyr => DOPA/EPI/NE;
Trp => serotonin,
Glu => GABA
Choline and acetyl-CoA in liver => acetylcholine
What is the role of glutamine in brain?
In brain, the formation of Gln remove ammonia & transport Glu within brain
What are the changes of amino acid metabolism relative to the postabsportive state?
High-protein meal: gut take/use Glu/Asp as fuel; liver claim AA to make glucose/proteins; sk. muscle oxidizes BCAAs
Hypercatabolic state/negative nitrogen balance: ↑ protein turnover/degradation
- Sepsis/trauma = enhance fuel/AA use for immune system/defense mechanism/wound healing
When does the body enter a catabolic state, characterized by negative nitrogen balance?
Sepsis (the presence of various pathogenic organisms, or their toxins, in the blood or tissues)
Trauma
Injury
Burns
In the fasting state, what is the state of glucose levels with alcoholic individuals?
Hypoglycemia
In the fed state, what is the state of glucose levels in alcoholic individuals?
Hyperglycemia -> glycolysis is also backed up!
