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M1 > AA and protein metabolism > Flashcards

AA and protein metabolism Flashcards

1
Q

THF

A

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)

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2
Q

Impairment of enzyme in THF derivative pathway

A

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.

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3
Q

B12 deficiency can cause what type of anemia?

A

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.

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4
Q

Folate deficiency

A

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)

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5
Q

Folate analogues

A

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)

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6
Q

S-adenosylmethionine (SAM)

A

Acts as a methyl group donor (i.e. DNA methylation and neurotransmitter synthesis)

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7
Q

Clinical relevance of SAM metabolism

A

Homocysteinemia/Homocystinuria (elevated HomoCys in blood and urine)

-Associated with increased risk of cardiovascular disease and thromboembolisms

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8
Q

When is Homocysteine produced?

A

Whenever s-adenosylmethionine is used as a methyl donor

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9
Q

Metabolic fates of HomoCysS

A
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10
Q

Causes of homocysteinemia/homocystuinuria

A
  1. 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)
  2. 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

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11
Q

Pernicious anemia (PA)

A

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

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12
Q

Organic acidemias

A

Rare inherited metabolic disorders due to inability to properly process specific amino acids or odder numbered fatty acids

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13
Q

Catabolism of ______ converge at priopionyl-CoA

A

Catabolism of Val, Ile, Thr, Met, odd-chain fatty acids and cholesterol (C-VOMIT)

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13
Q

Propionyl-CoA carboxylase (PCC)

A

Converts propionyl-CoA to methylmalonyl-CoA

Requires biotin (B7)

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14
Q

Propionic Acidemia (PA)

A

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

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15
Q

Methylmolonyl-CoA mutase (MUT)

A

Converts methylmalonyl-CoA to succinyl-CoA

Requires B12 (MUT and methionine synthase are the only two enzymes that require B12)

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16
Q

What enzymes require B12 as coenzyme?

A

Methylmalonyl-CoA mutase (MUT) and methionine synthase

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17
Q

Methylmalonyl acidemia (MMA)

A

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.

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18
Q

Maple Syrup Urine Disease (MSUD)

A

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.

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19
Q

How are BCAA’s toxic in MSUD?

A

Increased conc. of BCAA’s impairs large neutral AA transport (i.e. tyr, trp) into the brain -> decreased catecholamines, serotonin

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20
Q

Sxs of MSUD

A

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

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21
Q

Dx maple syrup urine disease (MSUD)

A

Newborn screening for elevated plasma BCAAs

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22
Q

Dx MMA

A

Dx: Increased MMA in serum and urine (can also have increased propionic acid levels). Newborn screening for elevated methylmalonyl-CoA derivative, methylmalonylcarnitine

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23
Q

Dx propionic acidosis

A

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)

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24
Q

Tyrosine synthesis

A

Produced from phenylalanine

Phenylalanine hydroxylase (PAH)

Requires tetrahydrobiopterin (BH4) which is convered to dihydrobiopterin (BH2)

BH2 reductase regenerates BH4 from BH2

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25
Q

Phenylketonuria (PKU)

A

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

26
Q

Aspartame and PKU

A

Aspartame contains phenylalanine (Asp-Phe methyl ester)

27
Q

PKU management

A

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)

28
Q

Maternal PKU

A

Excess Phe in mother can affect the fetus, potentially leading to intellectual disabilities, growth problems, and developmental delays (even if the fetus is heterozygous)

29
Q

Tyrosine Catabolism

A

Produces homogentisic acid (HGA) (aka alkpton)

30
Q

Alkaptonuria

A

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

31
Q

What are catecholamines derived from?

A

Tyrosine

32
Q

What are the catecholamines?

A

Dopamine/Epi/Norepi

In CNS - neurotransmitters
PNS - neurotransmitters and hormones

33
Q

Pathway of catecholamine synthesis

List products of each step

A

Tyr -> DOPA -> Dopamine -> Norepinephrine -> Epinephrine

Primarily occurs in the NS and adrenal medulla

34
Q

Tyrosine Hydroxylase

A

Catalyzes tyrosine to DOPA (requires tetrahydrobiopterin - BH4)

Rate-limiting step of catecholamine synthesis

35
Q

Catecholamine Synthesis

Diagram

A
36
Q

Most common cause of albinism

A

Deficiency of tyrosinase

(autosomal recessive)

Lack of pigmentation/Vision impairments

37
Q

What important biomolecules are derived from tryptophan?

A

Serotonin and melatonin

38
Q

What is melanin derived from?

Where is it found?

A

Tyrosine

(Tyr -> DOPA -> Dopaquinone ->->-> melanin)

Tyrosinase catalyzes the first two steps

Only found in melanocytes

39
Q

Function of tyrosinase in melanin production

A

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

40
Q

Synthesis pathway of serotonin and melatonin

A

Trp -> 5-hydroxytryptophan (5-HTP) -> Serotonin -> Melatonin

41
Q

Key enzyme in serotonin/melanin synthesis

A

Tryptophan hydroxylase (Trp -> 5-HTP)

Requires tetrahydrobiopterin (BH4)

Rate-limiting and regulatory step

Deficiency of this enzyme linked to depression, anxiety, and sleep disorders

42
Q

Niacin

A

B3 derived from tryptophan

Pathway isn’t sufficient to meet body’s needs, niacin from dietary sources is essential

43
Q

Why can B12 deficiency simultaneously cause homocysteinemia, megaloblastic anemia, and methylmalonic acidemia?

A

Because methionine synthase and methylmalonyl-CoA mutase both require B12

44
Q

Tetrahydrobiopterin

A

BH4: cofactor for hdyroxylation reactions, converted to BH2

BH2 converted back to BH4 by BH2 reductase to sustain further hydroxylation reactions

45
Q

BH2 Reductase Deficiency

A
46
Q

Pathways of homocysteine metabolism

A
47
Q

Study this

A

Same thing

48
Q

How can isoleucine enter the TCA cycle?

A

As acetyl CoA or succinyl CoA

49
Q

What cofactors does the branched chain alpha-keto acid dehydrogenase complex (BCKDC) require?

A

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

50
Q

AA metabolism that requires tetrahydrobiopterin

A
51
Q

Only strictly ketogenic amino acids

A

Leucine and lysine

52
Q
A

B12 for Met

B6 for Cys

53
Q
A

cystathionine beta-synthase

54
Q

An inability to synthesize tetrahydrobiopterin (BH4) would result in decreased levels of which of the following?

A

Serotonin

55
Q

Methotrexate, which is used to treat cancer and to slow the immune response in treating arthritis, is an analogue of which of the following?

A

Folate

56
Q

Epinephrine and melanin are derived from which of the following amino acids?

A

Tyrosine

57
Q

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?

A

branched-chain α-keto acid dehydrogenase

58
Q

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?

A

Homogentisate 1,2-dioxygenase deficiency

59
Q

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?

A

methylmalonyl-CoA mutase

60
Q

Why does high phenylalainine conc. prevent myelination in Pt’s with PKU?

A

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

61
Q

Overview of purine/pyrimidine synthesis

A

Includes the de novo pathways and the purine salvage pathway

62
Q

How is ribose-5-phosphate made?

A

From the HMP shunt

63
Q
A

M1 (30 decks)

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