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Carnitine Transport Deficiencies

Carnitine Transport Deficiencies. Lipid Metabolic Disorders SLC22 Transporters. 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

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Carnitine Transport Deficiencies

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  1. Carnitine Transport Deficiencies Lipid Metabolic Disorders SLC22 Transporters

  2. 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.

  3. 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

  4. carbamoyl phosphate synthetase-I activates acetyl-CoA + glutamate N-acetylglutamate + CoA N-acetylglutamate synthetase ●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

  5. 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

  6. 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)

  7. SLC22 Transporter Family Eur J Physiol (2004) 447:666-676 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

  8. SLC22 Structural Topology/Similarity Extracellular Glycosylated Domain, TMD 1 & 2 Eur J Physiol (2004) 447:666-676 Substrate Selectivity Na+ binding 12 TMD’s Intracellular Phosphorlation Domain, TMD 6 & 7

  9. ABCG5 ABCB4 ABCB11 hepatocyte Blood Bile cholesterol phospholipid OCT1 bile salts sinusoidal membrane canalicular membrane biliary micelle

  10. Kidney Transport Eur J Physiol (2004) 447:666-676

  11. Pharmacological Inhibitors of OCTN2 Quinidine anti-malarial / antiarrhymic Verapamil Ca2+ flux inhibitor antiangina / antiarrhymic Cephaloridine b-lactam antibiotic

  12. Competitive Inhibitors of OCTN2 Valproate TEA Organic Anion (OA) Organic Cation (OC) Carnitine Zwitterion

  13. J. Pharm. Exp. Ther., (2002), 302, 3, 1286

  14. Binding Site Speculation Based on Competition Expts OCTN2 J. Pharm. Exp. Ther., (2002), 302, 3, 1286

  15. Cell (2003), 111, 113-122

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