AA and protein metabolism Flashcards
THF
Tetrahydrofolate
Carries and transfers one-carbon units
Composed of pteridine ring + PABA + glutamate tail
Source: Dietary folate (B9) is reduced to dihydrofolate and then to THF by dihydrofolate reductase (DHFR)
Impairment of enzyme in THF derivative pathway
THF can accumulate in one form while the other form becomes deficient.
Sxs similar to dietary folate deficiency, but do not respond to folate supplementation.
B12 deficiency can cause what type of anemia?
Megaloblastic anemia, because THF becomes “trapped” as 5-CH3-THF (methionine synthase requires B12 to convert to THF) so the THF needed for thymidine synthesis can’t be produced in sufficient quantities to sustain DNA replication required for RBC production from precursors in bone marrow.
Folate deficiency
Neural tube defects - folate is crucial in DNA synthesis that is required for rapid cell division during early fetal development
Megaloblastic anemia - large dysfunctional immature RBC’s (Dx - low serum folate, elevated homocysteine)
Folate analogues
Used in the Tx of conditions characterized by rapidly dividing cells
Methotrexate - used to Tx various cancers, autoimmune disorders and ectopic pregnancies
Treimethoprim - used in combo with sulfamethoxazole (i.e. jirovecii pneumonia)
S-adenosylmethionine (SAM)
Acts as a methyl group donor (i.e. DNA methylation and neurotransmitter synthesis)
Clinical relevance of SAM metabolism
Homocysteinemia/Homocystinuria (elevated HomoCys in blood and urine)
-Associated with increased risk of cardiovascular disease and thromboembolisms
When is Homocysteine produced?
Whenever s-adenosylmethionine is used as a methyl donor
Metabolic fates of HomoCys
Causes of homocysteinemia/homocystuinuria
-
Deficiency of cofactor (B12, folate, or B6) required for HomoCys metabolism
-If folate or B12 deficient, HomoCys cannot be converted to Met - HomoCys conc. increases, Met conc. decreases, Cys may increase as HomoCys is shunted to the other pathway (Tx with folate/B12 supplementation)
-If B6 is deficient, HomoCys cannot be converted to Cys - HomoCys accumulates, Cys conc. decreases, Met levels increase as HomoCys is shunted to the other pathway (Tx with B6 supplementation) - Inherited deficiency of the enzymes of methionine cycle
-Autosomal recessive
-Sxs: tall stature, lens dislocation, thromboemoblisms, intellectual disability - variable expressivity
-Dx: ↑↑homocysteine, ↑↑methionine ↓cysteine in blood and urine. Genetic testing.
-Tx: Low-methionine diet, B6 supplementation, Cys becomes and essential AA
Pernicious anemia (PA)
Type of megaloblastic anemia due to an inability to properly absorb and utilize dietary B12
-Caused by lack of intrinsic factor (IF), which is producted by the parietal cells in the stomach and is essential for absorption of B12 in the small intestines
More common in the elderly (IF decrease with age)
Bariatric surgery and PPIs can cause IF deficiency that results in pernicious anemia
Vegans at risk
Organic acidemias
Rare inherited metabolic disorders due to inability to properly process specific amino acids or odd numbered fatty acids
Catabolism of ______ converge at priopionyl-CoA
Catabolism of Val, Ile, Thr, Met, odd-chain fatty acids and cholesterol (C-VOMIT)
Propionyl-CoA carboxylase (PCC)
Converts propionyl-CoA to methylmalonyl-CoA
Requires biotin (B7)
Propionic Acidemia (PA)
Build up of propionic acid in the blood
Caused by mutations in propionyl-CoA carboxylase - PCC (autosomal recessive)
Newborn sxs: metabolic acidosis, lethargy, poor feeding, vomiting, developmental delay (death if no intervention)
Organic acids, particularly PA and MMA, inhibit N-acetylglutamate synthase (NAGS). NAGS produces N-acetylglutamate, an essential activator of CPS I, the first enzyme in the urea cycle. This leads to hyperammonemia, which can cause severe neurological damage.
Management: Low-protein diet, supplementation with biotin and carnitine, NH3 scavengers
Methylmolonyl-CoA mutase (MUT)
Converts methylmalonyl-CoA to succinyl-CoA
Requires B12 (MUT and methionine synthase are the only two enzymes that require B12)
What enzymes require B12 as coenzyme?
Methylmalonyl-CoA mutase (MUT) and methionine synthase
Methylmalonyl acidemia (MMA)
Accumulation of methylmalonic acid in blood
Mutations in MUT genes, or in very rare cases, mutations in genes involved in B12 metabolism
Inheritance: autosomal recessive
Sxs: same as for newborns with propionic acidemia
Management: Strict diet that is low in Val, Ile, Thr, and Met. Carnitine supplement. B12 supplement for MMA due to defects in B12 metabolism.
Maple Syrup Urine Disease (MSUD)
Caused by mutations in branched-chain alpha-keto acid dehydrogenase (BKCD) genes - four genes
Inheritance: autosomal recessive
Accumulation of BCAA’s - (Val, Ile, Leu) and their corresponding toxic keto acids.
How are BCAA’s toxic in MSUD?
Increased conc. of BCAA’s impairs large neutral AA transport (i.e. tyr, trp) into the brain -> decreased catecholamines, serotonin
Sxs of MSUD
Newborns with poor feeding, vomiting, lethargy, dystonia, and a characteristic maple syrup urine ordor. Eventually seizures, apnea, cerebral edema.
Brain damage, coma, and death without prompt intervention
Management: Strict diet (low BCAA formula), thiamine supplementation
Dx maple syrup urine disease (MSUD)
Newborn screening for elevated plasma BCAAs
Dx MMA
Dx: Increased MMA in serum and urine (can also have increased propionic acid levels). Newborn screening for elevated methylmalonyl-CoA derivative, methylmalonylcarnitine
Dx propionic acidosis
Increased propionic acid in urine and serum.
Newborn screening for elevated levels of a propionyl-CoA derivative, propionylcarnitine (conjugation w/ carnitine is an alternative pathway activated to help remove excess propionyl-CoA)
