Amino Acid II Flashcards
Glucogenic AA’s Can be converted to what?
OAA, alpha-KG. succinyl-CoA, fumarate and pyruvate (all can be converted to OAA which can then go through GNG to give glucose)
Ketogenic AA’s can be converted to what?
form either acteyl-CoA and acetoacetyl-CoA; when acetyl-CoA levels are high in mito and OAA levels are low (due to GNG) then acetyl-CoA will condense to form ketone bodies
Purely Ketogenic AA’s
Leucine and Lysine
Purely glucogenic AA’s
Alanine, serine, cysteine, aspartate, asparagine, tryptophan, tyrosine, phenylalanine, valine, threonine, isoleucine, methionine, arginine, histidine, glutamine, glutamate, proline
AA’s that can be both glucogenic and ketogenic?
Phenylalanine, Tyrosine, tryptophan, isoleucine
Mitochondrial Glutamate Dehydrogenase Activity
particularly active in liver; activity of it influences overall rate of AA degradation; regulated by cellular charge energy; High levels of GTP/NADH inhibit enzyme; high levels of ADP activate enzyme
Familial Hyperinsulinemic Hypoglycemia Type 6
mutant forms of GDH that are insensitive to inhibition by GTP; leads to increase AA catabolism which results in elevated levels of both ATP and NH4+; this increased ATP causes pancreas to secrete insulin leading to hypoglycemia; increased glutamate degradation also reduce synthesis of N-acetylglutamate (activator of urea cycle) so there is increased NH4+ production and a reduction in capacity to eliminate it = hyperammonenima
Pyruvate: synthesis, fate,
from alanine, serine, glycine and cysteine; pyruvate either converted to acetyl-CoA or to OAA
Mito Glycine Cleavage System
major route of glycine catabolism; in mito in liver; 4 protein system in loose association w/ mito membrane; fully reversible rxn; Glycine + THF + NAD+ —-> NADH + CO2+ NH3 + N5, N10 methylene THF; defects in system lead to glycine encephalopathy;
Glycine Encephalopathy
defects in glycine cleavage system; aka nonketotic hyperglycemia; presents after birth; lethargy, lack of muscle tone, muscle twitching, may progress to death; treatment = reduction of glycine levels and management of seizures
Synthesis of OAA
from pyruvate (from serine, glycine, cysteine, alanine) or from asparagine and aspartate; Asparagine—-(asparaginase)—> Aspartate + NH4+ —(AST)—->OAA
Synthesis of Alpha-KG
Glutamate, glutamine, proline, arginine, ornithine, histidine; Glutamine—> Glutamate(also from proline, histidine or arginine)—>alpha-KG
Synthesis of propionyl-CoA
Isoleucine, threonine, methionine, valine; Carboxylation of propionyl-CoA in rxn that requires ATP, CO2 and biotin —> D-methylmalonyl-CoA—–(racemase)—> L-methylmalonyl-CoA—-(B12/Mutase)—> Succinyl-CoA
Propionic Acidemia
mutations in propionyl-CoA carboxylase
D-methylmalonic acidemia
mutations in racemase
methylmalonic aciduria
mutations in mutase ( or B12 deficiency)
Vitamin B12
only produced by bacteria; we get from meats/shellfish; plant foods DONT supply B12; binds to intrinsic factor (IF–produced by stomach); absorption occurs in ileum; after absorption, it binds to transport protein called transcobalamin for transport to tissues; liver stores 90% of body’s B12
Pernicious Anemia
functional deficiency due to body not being able to produce IF so body lacks ability to uptake B12
Megaloblastic Anemia
B12 deficiency; accumulate of N5-methyl THF will give rise to decrease in conc. of more oxidized forms of THF that are required for synthesis of thymidine and purine rings; lack of B12 = prevention of DNA replication; cells cant replicate so they reach a large size
Only Rxn that Can use N5-methyl THF as substrate?
conversion of homocysteine—–(methionine synthase)—> methionine; rxn has an ABSOLUTE requirement for B12
Demyelination Problems
actual of functional deficiency of B12; methionine synthase rxn plays key role since methionine administration to patients delays onset of neurological symptoms
2 Rxns in Body that Require B12?
1) Homocysteine + N5-methyl THF —> Methionine
2) L-methylmalonyl-CoA —-> succinyl-CoA
Megaloblastic Anemia: B12/Folate Deficieny?
can both due to both (chronic malnourishment–alcoholism) or one or the other; if it is due to deficiency in both then if you give folate sufficient THF is available for DNA synthesis and cell division can occur and anemia is resolved BUT if B12 issue is not fixed = demyelination and possibly brain/nerve damage and methylmalonyl acidemia remains
Demyelination due to lack of B12 model
lack of B12 causes reduction in homocysteine —-> methionine; less methionine means reduction in methionine—->S-adenosylmethionine; so all methionine is being bumped away from protein synthesis to be used for synthesizing SAM = demyelination
why is methionine essential AA if you can make it?
no good dietary sources of homocysteine
Homocysteine and Artherosclerosis
high levels of homocysteine are only a marker for heart disease that has already occurred based on evidence; supplementation of B vitamins for heart disease doesnt seem to slow progression of it
BCAAs?
Valine, Isoleucine, Leucine
Branched Chain Aminotransferases (BCAT) and Branched Chain alpha-Ketoacid dehydrogenase complex (BCKDH)
BCAT convert BCAA’s to corresponding alpha-ketoacids in muscle that are released into blood; BCKDH decarboxylates alpha-ketoacids in liver and other tissues;
Valine Degradation
BCAT gives alpha-ketoisovalerate; BCKDH gives propionyl-CoA
Isoleucine Degradation
BCAT gives alpha-keto-beta-methylglutarate; BCKDH gives propionyl-CoA/Acetyl-CoA
Leucine Degradation
BCAT gives alpha-ketoisocaproate; BCKDH gives acetyl-CoA and acetoacetate
Maple Syrup Urine Disease
defects in BCKHD; presence of branched chain alpha-ketoacids in urine; untreated = poor feeding, vomiting, slow/irregular breathing, ketoacidosis, hypoglycemia and neurodysfunction; treatment= managed diet w/ reduced BCAA’s; infant death in 4-7 days if untreated; neonatal screening performed
Tyrosinemia-II
keratitis; photophobia, painful skin lesions, intellectual disability; tyrosine aminotransferase defect
Alkaptonuria
urine turns black when exposed to air (oxidation of excreted homogentisate; black pigmentation of cartilage and collagen; joint destruction and arthritis; defect in Homogentisate oxidase; treatment directed towards reduction of homogentisate levels and administration of Nitisinone which inhibits formation of homogentisate
Tyrosinemia-I
severe condition affecting liver, kidneys and peripheral nerves; fatal at young age if untreated (liver failure); deficiency in Fumarylacetoacetate hydrolase so fumarylacetoacetate builds up which is converted to succinylacetone and found in urine;
3 Major Sources of Ammonium Ions
- generation of alpha-ketoacids (aminotransferase rxns)
- deamination of serine, cysteine, histidine and threonine
- glutaminase and asparaginase rxns on glutamine and asparagine
Mitchondrial Carbamoyl Phosphate Synthetase I: Substrates, Importance and Regulation
substrates= HCO3-, CO2, NH4+ and ATP; rate determining step of urea cycle; activated by N-acetylglutamate (produced by N-acetylglutamate synthetase which is stimulated by arginine);
Steps of Urea Cycle in Mitochondria and Enzymes and Why?
1st) HCO3-, NH4+, ATP, (CO2)—(CPS1)—>Carbamoyl Phosphate
2nd) Carbamoyl Phosphate + ornithine –(ornithine transcarbamoylase)–> citrulline (this leaves the mito in exchange for molecule of ornithine)
–this traps toxic NH4+ ions inside of mito so they cant diffuse out into blood stream
Steps of Urea Cycle in Cytoplasm
3rd) Aspartate + Citrulline —(argininosuccinate synthetase)—> argininosuccinate
4th) Argininosuccinate—(argininosuccinate lyase)—> Arginine + Fumarate
5th) Arginine—(arginase)—> Urea + ornithine
Intestinal-Renal Axis and Infants
several tissues can generate urea cycle intermediates (only liver can complete the cycle); small intestine cells can produce citrulline or ornithine from glutamine (orinthine will go to urea cycle); citrulline is picked up by kidney from circulation and converted to arginine; this is a post-natal process and isnt functioning in infants; adults usually can make enough arginine but infants cannot due to their positive nitrogen balance (growth) so arginine is essential for them; Arginine can become essential in adults if something is wrong w/ small intestine or kidney
Urea/TCA Bicycle
urea cycle produce fumarate which can be used by TCA cycle to produce more energy and urea cycle needs aspartate which can be produce by OAA from TCA cycle
Defects in Early Enzymes of Urea Cycle
early enzyme defects (carbamoyl phosphate synthetase I or ornithine transcarbamoylase) = very severe hyperammonemia; treatment = protein restriction (difficult b/c infant needs protein sources to grow), hemodialysis, administration of phenylbutyrate (forms water soluble conjugate w/ glutamine) and benzoate (forms water soluble conjugate w/ glycine) this pulls nitrogen from usual urea cycle precursors into glycine and glutamine and are eliminated
Defects in Later Enzymes of Urea Cycle
defects in later cycle enzymes are not as severe (intermediates are less toxic and excreted in urine); treated w/ dietary intervention;
Liver Disease Problems and Treatments
dysfunction of urea cycle; bacteria in gut generate ammonia which would normally pass into portal hepatic circulation and converted to glutamine in liver then urea; process impaired in patients w/ liver diesase; treatment involves trying to take load off of the liver (antibiotic to cut back on NH4+ producing bacteria ex.)
Argininosuccinic aciduria
argininosuccinate lyase deficiency treated w/ arginine to support continued citrulline synthesis b/c supplemental arginine will be used to form ornithine which can go back in urea cycle
Citrullinemia
defect in argniniosuccinate synthetase; citrulline eliminated as waste nitrogen (however, only carries 1 of the waste nitrogens); treatment = give arginine to support citrulline synthesis; give phenylbutyrate too
Consequences of Hyperammonemia
ammonia = neurotoxin; lethargy, stupor, convulsions, death; brain swelling in astrocytes; increased ammonia leads to more glutamine synthesis and high levels of glutamine may cause osmotic flux into brain causing swelling; Wilson may not believe this
Fed State and AA Catabolism
In fed state, catabolized AA’s are ultimately used for glucose production to supply glycogen build up and fatty acid synthesis that go to TAG storage
Starvation State and AA Catabolism
muscle protein breakdown provides AA’s for GNG and energy generation (TCA cycle); after glycogen stores used up (10-12 hrs.) GNG needs to take place; liver gets carbon skeletons from catabolism of skeletal muscle protein for GNG; skeletal muscle rich in BCAA’s; alanine and glutamine released in greatest quantity from skeletal muscle
Action of BCAT on BCAA’s is a major source of?
Nitrogen for production of glutamine and alanine in muscle
