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)
Tyrosine synthesis
Produced from phenylalanine
Phenylalanine hydroxylase (PAH)
Requires tetrahydrobiopterin (BH4) which is convered to dihydrobiopterin (BH2)
BH2 reductase regenerates BH4 from BH2
Phenylketonuria (PKU)
Mutations in PAH (97% of cases) or BH2 reductase
Sxs: Neonatal onset with intellectual disability, sezures, light skin/hair, mousey/musty odor
-Phe is converted to phenylpyruvate and phenylacetate leading to a musty odor
-Phe impairs large neutral AA transport into brain -> decreased catecholamine and serotonin -> neurological sxs
Dx: screen for phenylalanine elevation
Aspartame and PKU
Aspartame contains phenylalanine (Asp-Phe methyl ester)
PKU management
Low phe diet, tyrosine supplementation (without PAH, tyr becomes an essential AA)
Kuvan (sapropterin): synthetic tetrahydrobiopterin
Palnziq (pegvaliase-pqpz): SQ injectable recombinant phenylalanine ammonia lyase (PAL) enzyme (converts phe to ammonia and tran-cinnamic acid to lower blood phe levels)
Maternal PKU
Excess Phe in mother can affect the fetus, potentially leading to intellectual disabilities, growth problems, and developmental delays (even if the fetus is heterozygous)
Tyrosine Catabolism
Produces homogentisic acid (HGA) (aka alkpton)
Alkaptonuria
Accumulation of HGA in urine
Inheritance: autosomal recessive
sxs: HGA accumulates and is deposited in connective tissue, leading to darkening of the skin, cartilage, and other tissues (ochronosis). HGA is also exreted in the urine, causing it to turn dark brown or black when exposed to air (alkaptonuria is also called dark urine disease). Over time, alkaptonuria can lead to progressive, degenerative arthritis
Dx: dark urine upon standing, elevated HGA in urine
Management: Dietary protein restriction, pain management for arthritis
What are catecholamines derived from?
Tyrosine
What are the catecholamines?
Dopamine/Epi/Norepi
In CNS - neurotransmitters
PNS - neurotransmitters and hormones
Pathway of catecholamine synthesis
List products of each step
Tyr -> DOPA -> Dopamine -> Norepinephrine -> Epinephrine
Primarily occurs in the NS and adrenal medulla
Tyrosine Hydroxylase
Catalyzes tyrosine to DOPA (requires tetrahydrobiopterin - BH4)
Rate-limiting step of catecholamine synthesis
Catecholamine Synthesis
Diagram
Most common cause of albinism
Deficiency of tyrosinase
(autosomal recessive)
Lack of pigmentation/Vision impairments
What important biomolecules are derived from tryptophan?
Serotonin and melatonin
What is melanin derived from?
Where is it found?
Tyrosine
(Tyr -> DOPA -> Dopaquinone ->->-> melanin)
Tyrosinase catalyzes the first two steps
Only found in melanocytes
Function of tyrosinase in melanin production
Tyrosine to DOPA: Hydroxylation of tyrosine to L-DOPA (uses copper not BH4 as cofactor)
DOPA to dopaquinone: Oxidation of L-DOPA to dopaquinone
Tyrosinase is a rate-limiting enzyme for the conversion of tyr to melanin
Synthesis pathway of serotonin and melatonin
Trp -> 5-hydroxytryptophan (5-HTP) -> Serotonin -> Melatonin
Key enzyme in serotonin/melanin synthesis
Tryptophan hydroxylase (Trp -> 5-HTP)
Requires tetrahydrobiopterin (BH4)
Rate-limiting and regulatory step
Deficiency of this enzyme linked to depression, anxiety, and sleep disorders
Niacin
B3 derived from tryptophan
Pathway isn’t sufficient to meet body’s needs, niacin from dietary sources is essential
Why can B12 deficiency simultaneously cause homocysteinemia, megaloblastic anemia, and methylmalonic acidemia?
Because methionine synthase and methylmalonyl-CoA mutase both require B12
Tetrahydrobiopterin
BH4: cofactor for hdyroxylation reactions, converted to BH2
BH2 converted back to BH4 by BH2 reductase to sustain further hydroxylation reactions
BH2 Reductase Deficiency
Pathways of homocysteine metabolism
Study this
Same thing
How can isoleucine enter the TCA cycle?
As acetyl CoA or succinyl CoA
What cofactors does the branched chain alpha-keto acid dehydrogenase complex (BCKDC) require?
Five cofactors: thiamine (B1), lipoic acid, CoA (B5), FAD (B2), and NAD (B3)
TLC For Nancy
Thiamine/Lipoic acid/CoA/FAD/NAD
Deficiency of BCKDC = Maple syrup
AA metabolism that requires tetrahydrobiopterin
Only strictly ketogenic amino acids
Leucine and lysine
B12 for Met
B6 for Cys
cystathionine beta-synthase
An inability to synthesize tetrahydrobiopterin (BH4) would result in decreased levels of which of the following?
Serotonin
Methotrexate, which is used to treat cancer and to slow the immune response in treating arthritis, is an analogue of which of the following?
Folate
Epinephrine and melanin are derived from which of the following amino acids?
Tyrosine
A mother with a 3-month-old baby tells you (the pediatrician) that the infant is lethargic and has poor suckling and seems uninterested in eating. In addition, the mother notes that the baby’s diapers often smell like maple syrup. This infant likely has a defect in which of the following enzymes?
branched-chain α-keto acid dehydrogenase
A 40-year-old patient presents to the clinic with complaints of darkening urine, particularly noticeable after it has been exposed to air. The patient has also noticed that their skin, sclera (white of the eye), and the cartilage of their ears have become progressively darker over the years. Physical examination reveals dark pigmentation in the mentioned areas. Laboratory analysis of the urine shows that it darkens upon exposure to air and turns black when alkaline solutions are added. This patient’s condition is likely the result of which of the following?
Homogentisate 1,2-dioxygenase deficiency
aka alkaptonuria
A 2-month-old child is brought to the emergency department by parents who report a history of poor feeding, vomiting, and developmental delays. The child appears pale, lethargic, and irritable. Laboratory tests reveal metabolic acidosis, anemia, and elevated levels of methylmalonic acid in the blood and urine. Further testing will most likely confirm a deficiency in which enzyme?
methylmalonyl-CoA mutase
Why does high phenylalainine conc. prevent myelination in Pt’s with PKU?
Becuase elevated levels of Phe will disrupt AA transport
Neutral transporter becomes “clogged” with phenylalanine and other AA’s are unable to bind with transporter - Kmm for Phe to transporter is ~0.3 µmol/L whereas other neutral AA’s are around 1-1.5 µmol/L
Overview of purine/pyrimidine synthesis
Includes the de novo pathways and the purine salvage pathway
How is ribose-5-phosphate made?
From the HMP shunt
Cystathionine synthase deficiency presentation
Homocystinuria
Stroke, Marfanoid habitus (tall, high-arched palate, arachnodactyly), inferonasal lens subluxation, and intellectual disability.
Homocysteine is thrombogenic - predisposition to thromboembolic events
Caused by decreased affinity of cystathionine synthase to bind B6
Can be Tx’d by supplementation of B6
