Carnitine Transport Deficiencies

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Carnitine Transport Deficiencies
Lipid Metabolic Disorders SLC22 Transporters
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Carnitine
? 75 provided in diet 25 synthesized in
liver - meat, poultry, fish dairy
products - 70 80 of dietary intake is
absorbed ? Carnitine is used to regulate levels
of acyl-CoA inside cells - CoA pools are
limited and CoA is needed in other
processes (GNG, CAC, Urea cycle, b-ox) -
Transfer acyl to carnitine to restore CoA pools
so the acyl-carnitine serve as a reservoir of
activated acyl groups.
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Urea Cycle
regulated step
excreted in urine
emphasis on green text added
To CAC
Adapted from http//web.indstate.edu/thcme/mwking/
nitrogen-metabolism.html
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? Without restoration of CoA pools, ? Acetyl-CoA
levels drop ? N-acetylglutamate (NAG) will not be
made ? CPS I will not be activated and so urea
cycle will not proceed ? NH4 builds up
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Primary Carnitine Deficiency
? aka Plasmalemmal Carnitine Transporter
Defect ? cardiomyopathy (disease of heart
muscle) Late infancy or early childhood (1 7
years) ? hypoglycemic, hypoketotic
encephalopathy (disorder of brain) 1 month 5
years of age ? responds to carnitine
supplementation suspected compensation by
other transporters
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Primary Carnitine Deficiency
? Defect in active transport of carnitine across
the cell membrane ? from blood into cell ?
by OCTN2 a member of the SLC22 family of
transporters (1) renal reabsorption is
impaired (2) tissues are unable to concentrate
carnitine (heart, muscle, fibroblasts) reason
limited improvement seen if plasma
carnitine supplemented to normal (must be
higher)
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SLC22 Transporter Family
Eur J Physiol (2004) 447666-676
1) Electrogenic 2) Na indep 3) reversible
1) OC uniport 2) H/OC antiport 3) Na/Carn
cotrans
1) Reversible 2) Cotransport 3) Divalent OC
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SLC22 Structural Topology/Similarity
Extracellular Glycosylated Domain, TMD 1 2
Eur J Physiol (2004) 447666-676
Substrate Selectivity
Na binding
12 TMDs
Intracellular Phosphorlation Domain, TMD 6 7
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hepatocyte
Blood
Bile
cholesterol
phospholipid
OCT1
bile salts
sinusoidal membrane
canalicular membrane
biliary micelle
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Kidney Transport
Eur J Physiol (2004) 447666-676
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Pharmacological Inhibitors of OCTN2
Quinidine anti-malarial / antiarrhymic
Verapamil Ca2 flux inhibitor antiangina /
antiarrhymic
Cephaloridine b-lactam antibiotic
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Competitive Inhibitors of OCTN2
Valproate
TEA
Organic Anion (OA)
Organic Cation (OC)
Carnitine
Zwitterion
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J. Pharm. Exp. Ther., (2002), 302, 3, 1286
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Binding Site Speculation Based on Competition
Expts
OCTN2
J. Pharm. Exp. Ther., (2002), 302, 3, 1286
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(No Transcript)
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Cell (2003), 111, 113-122