Lecture 58

Question 1

degradation of glucogenic AAs

Answer 1

• each AA has its own pathway, but all glucogenic eventually produce parts of TCA cycle
• Thr, Gly, Trp, Ala, Ser, Cys become pyruvate
• Asp, Asn become oxaloacetate
• Asp, Tyr, Phe become fumarate
• Val, Thr, Ile, Met become propionyl CoA (eventually succinyl CoA)
• Arg, His, Gln, Pro, Glu become α-ketoglutarate

pg 1504

Question 2

degradation of ketogenic AAs

Answer 2

• Lys becomes acetyl-CoA
• Leu becomes HMG-CoA (and eventually acetoacetate)

pg 1505

Question 3

synthesis of nonessential AAs

Answer 3

• phosphoglycerate → Ser → Gly; Ser + Met → Cys
• pyruvate → Ala
• Phe → Tyr (intracellularly)
• oxaloacetate → Asp; Asp + Gln → Asn
• α-ketoglutarate → Glu → glutamate semialdehyde → Pro, Arg; Glu → Gln

pg 1506

Question 4

one-carbon donors: tetrahydrofolate

Answer 4

• active form of folic acid, also called FH₄ or THF
• responsible for one-carbon pool which is required for conversion of some AAs (formyl, methylene, methyl)

pg 1507

Question 5

one-carbon donors: vitamin B₁₂ (cobalamine)

Answer 5

donates in only 2 reactions:

• synthesis of methionine: homocysteine to methionine uses methyl-cobalamin
• odd numbered FA, some AA degradation: methylmalonyl CoA to succinyl CoA uses adenosyl-cobalamin

pg 1508

Question 6

one-carbon donors: s-adenosylmethionine (SAM)

Answer 6

• norepinphrine → epinephrine
• guanidinoacetate → creatine
• nucleotides → methylated nucleotides
• phosphatidylethanolamine → phosphatidylcholine
• acetylserotonin → melatonin

pg 1509

Question 7

relationship between one-carbon donors

Answer 7

• FH₄ * CH₃ requires B₁₂ for conversion to FH₄
• B₁₂ * CH₃ requires SAM donors from homocysteine for conversion to B12

pg 1510

Question 8

folate trap in vitamin B₁₂ deficiency

Answer 8

• N5-methyl form of THF in the B12-dependent methylation of Hcy to methionine is impaired
• because the methylated form cannot be converted directly to other forms of THF, folate is trapped in the N5-methyl form, which accumulates
• levels of other forms decrease
• cobalamin deficiency leads to a deficiency of the THF forms needed in purine and TMP synthesis, resulting in the symptoms of megaloblastic anemia (functional folate deficiency)

pg 1510

Question 9

hyperhomocysteinemia

Answer 9

• homocysteine (Hcy) is produced during methionine metabolism
• two major disposal pathways for Hcy requiring vitamins B₁₂ and B₆ (PLP)
• deficiencies of either of both leads to Hcy elevation
• elevations in plasma Hcy levels promote oxidative damage, inflammation, and endothelial dysfunction and are an independent risk factor for occlusive vascular disease
• elevated homocysteine levels have been linked to CVD and neurologic disease
• elevated Hcy during pregnancy is associated with increased incidence of neutral tube defects (via folic acid)

pg 1511

Question 10

disposal pathways of Hcy

Answer 10

• two major disposal pathways
• conversion to Met requires folate and vitamin B12-derived coenzymes and is a remethylation process
• formation of Cys requires vitamin B6 (pyridoxine) and is a transsulfuration process -> sulfur of Met becomes sulfur of Cys

pg 1511

Question 11

overview of AA metabolic defects

Answer 11

• single gene mutations
• loss of function disorder in their enzymes
• collectively represent a lot of pediatric diseases
• newborn screening for most done roughly 24 hrs after first feeding
• early diagnosis is critical → treatment is dietary restriction for most
• most common: cystinuria
• benign condition (clinically insignificant): histidinemia and cystathioninuria

pg 1512

Question 12

phenylketonuria (PKU)

Answer 12

• 1 in 1500 births
• classical PKU (98%) → deficiency of PAH (phenylalanine hydroxylase)
• deficiency of BH₄ (2%) → deficiency of enzymes synthesizing BH₄ (less common form)

pg 1513

Question 13

normal phenylalanine metabolism

Answer 13

• phenylalanine converted to tyrosine
• tyrosine precursor for tissue proteins, melanin, catecholamines, and fumarate acetoacetate
• normal serum levels of phenylalanine: less than 2 mg/dL

pg 1514

Question 14

classic phenylketonuria

Answer 14

• autosomal recessive disorder
• phenylalanine converted to phenylpyruvate forming phenylketones
• phenylketones and phenylalanine accumulate in tissues, blood, and urine
• hyperphenylalaninemia → elevated Phe in blood (>10mg/dL → 10-20 is mild, >20 is severe)
• deficiency of Tyr and respective products
• presence of phenylketones give the urine a characteristic musty odor

pg 1515-1516

Question 15

clinical manifestations of classic PKU

Answer 15

• CNS: normal at birth, begin to show signs within first few months; severe intellectual disability, developmental delay, microcephaly, and seizures if not treated
• hypopigmentation: fair hair, light skin color, and blue eyes; Tyr is decreased which results in decreased synthesis of melanin
• GI symptoms: vomiting, sometimes severe enough to be misdiagnosed as pyloric stenosis, may be an early symptom

pg 1517

Question 16

diagnosis of classical PKU

Answer 16

• neonatal screening
• additional testing to confirm
• prenatal diagnosis is available if family history is evident

pg 1517

Question 17

treatment of classical PKU

Answer 17

dietary restriction of Phe at all stages of life including pregnancy

pg 1517

Question 18

BH₄ deficiency

Answer 18

• a deficiency of any of the BH4 synthesis enzymes leads to hyperphenylalaninemia and decreased synthesis of catecholamines and serotonin
• simply restricting dietary Phe does not reverse the CNS effects due to deficiencies in neurotransmitters
• supplementation with BH₄ and replacement therapy of the products of the affected enzymes may improve the clinical outcome
• response is usually unpredictable and variable
• increased maternal Phe in blood is teratogenic to fetus

pg 1519

Question 19

melanin and skin color

Answer 19

• pathway uses tyrosinase which is a copper-requiring enzyme
• two types of eumelanin: DHICA-melanin which is brown and DHI-melanin which is black
• also pheomelanin which is yellow/red

pg 1520-1521

Question 20

Menkes disease

Answer 20

• mutations in the ATP7A gene (PM Cu²⁺ transporter)
• symptoms: hypotonia, sagging facial features, intellectual disability, and developmental delay; pale skin with light hair color (due to melanin synthesis requiring copper), sparse and fragile kinky hairs (kinky hair disease)

pg 1522

Question 21

oculocutaneous albinism (OCA): OCA1A

Answer 21

• tyrosinase is defective
• COMPLETE absence of tyrosinase activity and melanin production
• retention of misfolded tyrosinase protein within the Er

pg 1523

Question 22

oculocutaneous albinism (OCA): OCA2

Answer 22

• P protein defective
• melanosomal transmembrane protein also present in the ER
• functions include regulating organelle pH, facilitating vacuolar accumulation of glutathione, and processing/trafficking of tyrosinase

pg 1523

Question 23

oculocutaneous albinism (OCA)

Answer 23

• defects in a number of enzymes or proteins involved in the production and cellular distribution of melanin
• most severe form is complete albinism → OCA1 (TYR mutations) in which the deficiency is in the enzyme tyrosinase and results in complete lack of pigment
• patients have an increased risk of skin cancer and need to constantly be protected from sunlight

pg 1524

Question 23

tyrosinemia type I

Answer 23

• defects in fumaryl-acetoacetate hydrolase
• severe multisystemic disease involving liver, kidney, nerves
• damage is caused by fumarylacetoacetate and succinylacetone accumulation
• treatments: diet low in Phe and Tyr can slow down progression, medication (nitisinone → NTBC) inhibits degradation pathway of Tyr to fumarylacetate
• characteristic cabbage-like odors, liver failure and renal tubular acidosis
• other rare types: type II and type III

pg 1526

Question 24

alkaptonuria

Answer 24

• deficiency of homogentisate oxidase (HO) → involved in breakdown of tyrosine
• relatively benign condition
• patients urine will turn black upon standing for a period of time, reflective of oxidation of homogentisic acid (HA) in the urine
• black pigmentation (ochronosis) of cartilage and collagenous tissue
• serious problem is arthritis (can be severe)
• treatment: diets low in protein, especially Phe or Tyr, can help

pg 1525

Question 25

homocystinuria

Defects of Met metabolism

Answer 25

• classic form due to deficiency in cystathionine synthase (conversion of homocysteine to cystathionine)
• accumulation of homocysteine occurs in the urine
• Met and Hcy are elevated in the blood; Cys is low
• skeletal abnormalities, increased risk of clotting, lens dislocation, and intellectual disability occur

pg 1527

Question 26

cystathioninuria

Defects of Met metabolism

Answer 26

• accumulation of cystathionine and its metabolites
• rare deficiency in cystathionase
• benign condition → no clinical significance

pg 1528

Question 27

methylmalonic acidemia

Defects of Met metabolism

Answer 27

• deficiency in methylmalonyl CoA mutase or adenosylcobalamin
• elevated levels of methylmalonic acid occur in the blood
• metabolic acidosis and developmental problems occur
• intermediate in conversion of propionyl CoA (from odd-chain FAs, Val, Ile, Met, and Thr) to succinyl CoA

pg 1529

Question 28

maple syrup urine disease (MSUD)

Answer 28

• deficiency in BCKD (branched-chain alpha-keto acid dehydrogenase)
• Ile in urine gives it its characteristic smell maple syrup-like odor
• symptoms: feeding problems, vomiting, ketoacidosis, changes in muscle tone, neurologic problems that can result in coma (due to Leu rise)
• treatment: synthetic formula free of BCAAs
• classification:
• ….. classical, neonatal-onset form: most common; leukocytes or cultured skin fibroblasts show little or no BCKD activity; infants show symptoms in first few days of life; if not diagnosed and treated, lethal in first weeks of life
• ….. variant forms: up to 30% of normal BCKD activity present; symptoms are milder and show an onset from infancy to adolescence

pg 1531