Lecture 58 Flashcards
Amino Acids Metabolism and Metabolic Defects
1
Q
degradation of glucogenic AAs
A
- 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
2
Q
degradation of ketogenic AAs
A
- Lys becomes acetyl-CoA
- Leu becomes HMG-CoA (and eventually acetoacetate)
pg 1505
3
Q
synthesis of nonessential AAs
A
- 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
4
Q
one-carbon donors: tetrahydrofolate
A
- 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
5
Q
one-carbon donors: vitamin B12 (cobalamine)
A
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
6
Q
one-carbon donors: s-adenosylmethionine (SAM)
A
- norepinphrine → epinephrine
- guanidinoacetate → creatine
- nucleotides → methylated nucleotides
- phosphatidylethanolamine → phosphatidylcholine
- acetylserotonin → melatonin
pg 1509
7
Q
relationship between one-carbon donors
A
- FH4 * CH3 requires B12 for conversion to FH4
- B12 * CH3 requires SAM donors from homocysteine for conversion to B12
pg 1510
8
Q
folate trap in vitamin B12 deficiency
A
- 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
9
Q
hyperhomocysteinemia
A
- 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
10
Q
disposal pathways of Hcy
A
- 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
11
Q
overview of AA metabolic defects
A
- 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
12
Q
phenylketonuria (PKU)
A
- 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
13
Q
normal phenylalanine metabolism
A
- 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
14
Q
classic phenylketonuria
A
- 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
15
Q
clinical manifestations of classic PKU
A
- 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
16
Q
diagnosis of classical PKU
A
- neonatal screening
- additional testing to confirm
- prenatal diagnosis is available if family history is evident
pg 1517
17
Q
treatment of classical PKU
A
dietary restriction of Phe at all stages of life including pregnancy
pg 1517
18
Q
BH4 deficiency
A
- 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
19
Q
melanin and skin color
A
- 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
20
Q
Menkes disease
A
- 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
21
Q
oculocutaneous albinism (OCA): OCA1A
A
- tyrosinase is defective
- COMPLETE absence of tyrosinase activity and melanin production
- retention of misfolded tyrosinase protein within the Er
pg 1523
22
Q
oculocutaneous albinism (OCA): OCA2
A
- 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
23
Q
oculocutaneous albinism (OCA)
A
- 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
23
Q
tyrosinemia type I
A
- 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
24
Q
alkaptonuria
A
- 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
25
Q
homocystinuria
Defects of Met metabolism
A
- 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
26
Q
cystathioninuria
Defects of Met metabolism
A
- accumulation of cystathionine and its metabolites
- rare deficiency in cystathionase
- benign condition → no clinical significance
pg 1528
27
Q
methylmalonic acidemia
Defects of Met metabolism
A
- 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
28
Q
maple syrup urine disease (MSUD)
A
- 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
