1. CARNITINE Gamma-hydroxi-N- trimethylamino-butyrate

2. Sources of blood carnitine: a.) mainly animal source food: 1-8 %, 300 μmole/day b.) we synthesize in liver (brain, kidney): 1-2%, 100 μmoles/day c.) in kidney absorbed from the filtrate to the blood: 92-98% (most important) Excretion - by urine 400 μmoles/day -through gut: changable amount Tissue content blood plasm 300 μmoles/5 liters, 40-60 μmoles/L skeletal muscle 2000-3000 μmoles/kg liver, heart 800-1500 μmoles/kg other tissues 600-700 μM all carnitine in tissues 50000 μmoles

3. Carnitine concentration is bigger in every cells than in blood, therefore the entrance is always active transport, the departure is passive. Carnitine is ionic (zwitter ion), so it requires in every membrane (plasma, mitochondria, ER) a protein transporter. Synthesis Last step is only in liver (brain and kidney insufficient amount).  Starts from proteins, on Lys  Localization of steps one after each other: nucleus, lysosome, mitochondria, cytoplasm  Requires: SAM (Met), Lys, ascorbate, PLP, NAD, enzymes a) Vitamin or enzyme deficiency leads to improper synthesis, but food carnitine is enough. b)Strict vegetarian people can not eat high amount, but absorption from gut becomes more efficient. c)When carnitine transporter in the kidney does not function, carnitine is exreted by the urine, causing systemic carnitine deficiency in all the body.

4. Lys és Met: essencial amino acids B6-vitamin l the last step is sufficient only in liver small amount in brain,kidney ascorbate B3-vitamin

5. Carnitine transporters in the membranes 1.) OCTN2 = organic cation transporter(uniporter) = high affinity carnitine/Na+ symporter Kt = 1-6 microM carnitine reabsorption from the filtrate to the blood in the apical tubular cells in kidney carnitine entrance from blood to cells: skel. mucle, heart, pancreas, placenta, brain, lung, testis, fibroblast OCTN2 transporter protein hereditary deficiency leads to systemic carnitine deficiency 2.) OCTN3 = intermediate affinity carnitine specific uniporter Kt= 20 μM spermium, liver peroxisome 3.) OCT 1,2,3 = intermediate affinity organic cation uniporters or exchangers basal membrane of tubular cells in kidney, intestine, muscle, testis

6. 4.) OCTN1 = low affinity organic cation/ H+ antiporter Kt > 500 μM in kidney proximal tubules acyl-carnitines: alkaloids, medicines etc. are exreted to filtrate lung, bone marrow, prostate, placenta, pancreas, heart, uterus, spleen, testis... in mitochondrial inner membrane 5.) ATB o,+ is a basic amino acid uniporter Kt = 0.8 mM lung, intestine, mammary gland 6.) small affinity carnitine/Na+ symporter = high affinity gamma-butyrobetain/Na+ symporter in liver, brain Carnitine is synthesized from gamma-butyrobetain in one step.

7. = OCTN1 acyl-carnitine carnitine

8. Function of carnitine 1.) Entrance of LCFA (long chain fatty acids) to mitochondria, ER, peroxisome 2.) Leaving of SC(F)A short chain acids from cell organells and cells to excrete out of the cells and the body (as acyl-carnitine). In case of OCTN2 hereditary deficiency carnitine can not be reabsorbed from filtrate, rather it is flowed out of the body, causing systemic deficiency.

9. Function of carnitine: to transport fatty acids into and out of cell organells VLC = very long chain CAC = carnitine/acyl-carnitine translocase

10. c)No enough acetyl-CoA for citric acid cycle and activation of pyruvate carboxylase, gluconeogenesis does not proceed, glucose is not replenished. d)In starvation in liver no ketone body synthesis (from FA derived acetyl-CoA), so the brain can not gain them instead of glucose. e)Heart always oxidizes FAs, skeletal muscle uses FAs in resting and long term exercise. Without FA beta-oxidation no enough ATP for movement, causing tiredness, heart hyperthrophy, progressing cardiomyopathy, death of2-4 years old child f)FAs can not enter to cell organells, they are accumulated in cytoplasm activating TAG synthesizing enzymes, causing lipid degeneration in liver, heart, muscle Never nowhere fatty acids can enter to mitochondria to be oxidized, therefore: a)always everywhere glucose (and amino acids) are degraded to yield energy, glucose is consumed very fast, causing between meals life threatening hypoglycemia, coma b)in liver, muscle etc. PDHC is not inhibited by acetyl-CoA (from FA oxidation) during fasting, glucose is not spared for obligate glucose consuming tissues Signs of systemic carnitine deficiency

11. Therapy Big dose of oral carnitine during the whole life for little affinity carnitine transporters to work. 5% of normal concentration in cells is enough.