Medical Biochemistry: Fatty Acid Oxidation PDF

MEDICAL BIOCHEMISTRY Fatty Acid Oxidation Oxidization of FA Objectives: Student Learning Outcomes: Describe the role of the ER and peroxisome for FA oxidization Unsaturated FA: require additional reactions Odd numbered FA MCFA SCFA VLCFA Branched chain FA But… there is more Enzymes specific for diff...

MEDICAL BIOCHEMISTRY Fatty Acid Oxidation Oxidization of FA Objectives: Student Learning Outcomes: Describe the role of the ER and peroxisome for FA oxidization Unsaturated FA: require additional reactions Odd numbered FA MCFA SCFA VLCFA Branched chain FA But… there is more Enzymes specific for different fatty acid chain lengths catalyze βoxidation spiral Chain length specificity In general LCFA are transferred from enzymes that act on longer chains to those that act on shorter chains Medium and short chain fatty acylCoA may be formed or transferred from peroxisomes and enter the spiral at the enzyme that is most active for FA for their chain length Oxidation of odd-chain Fatty acids C-C-C-C-C-C-C-C-C-C-C-C-C-C-C Oxidation of odd chainlength fatty acids: C-C-C-C-C-C-C-C-C-C-C-C-C Yields 1 propionyl CoA, rest Acetyl CoA C-C-C-C-C-C-C-C-C-C-C C-C-C-C-C-C-C-C-C C-C-C-C-C-C-C C-C-C-C-C Figs. 10,11 C-C C-C-C Oxidation of oddchain Fatty acids 3 enzymes required to process propionyl-CoA 1st step: propionyl-CoA is carboxylate (via carboxylase) to form D-methylmalonyl-CoA, with biotin as a cofactor that transfers CO2 or HCO3- to propionate The D- form is converted to the L form via an epimerase Intramolecular rearrangement of L-Methylmalonyl-CoA forms Succinyl-CoA via mutase that requires B12 More water-soluble, not stored in adipose tissue After meal: Enter blood, into liver; transported to mitochondrial matrix by transporters (monocarboxylate transporter). Activated to acyl CoA derivatives; β-oxidation MCL acyl CoA synthetase has broad specificity, including carboxyl groups: Forms acyl CoAs with salicylate (aspirin), valproate and benzoate These are conjugated to glycine, excreted urine Medium chain fatty acids Medium chain fatty acids An increase in MCFA or SCFA acylglycine in the urine with acylcarnitines or dicarboxylic acids may indicate a fatty acid disorder Example: A patient with medium-chain acyl-CoA dehydrogenase (MCAD) deficiency will have Octanoylglycine in their urine. This is a common deficiency Alternate routes of Fatty Acid oxidation Peroxisomal β- oxidation – very long-chain F.A. Peroxisomal α-oxidation – branched, CH3- F.A. Microsomal ω-oxidation - in ER VLCFA 1st enz oxidase -> H2O2 Neutralized by catalase no energy Contrast with β-oxidation Fig. 13 Oxidation of VLCFA in peroxisome Peroxisome oxidizes VLCFA by β-oxidation: forms 1 H2O2, 1 Acetyl CoA, 1 NADH per spiral; 4 enzymes: 1. oxidase (generates H2O2) 2. Enoyl-CoA hydratase (adds water)Convert 3. Hydroxyacyl CoA dehydrogenase (donates e- to NAD+) 4. Thiolase – forms acetyl-CoA COT (carnitine octanoyltransferase) CAT (acetylcarnitine transferase) translocase CoA to carnitine translocase Oxidation of VLCFA in peroxisome Acetyl CoA, MCFA or SCFA go to mitochondria to complete oxidation SCFA carnitine converted back to CoA by CAT or CPTII Convert CoA to carnitine Hydrogen peroxide is neutralized in peroxisomes Peroxisomes are present in almost every cell Fatty acyl-CoA oxidase generates H2O2 H2O2 is neutralized in peroxisome by catalase that converts it to water and oxygen Peroxisome enzymes must be confined to peroxisomes α oxidization in peroxisome Phytanic acid is found in fish and dairy products α oxidization occurs prior to β-oxidization in peroxisome Presence of a methyl group on the βC prevents βoxidization. Fatty acids must first be broken down by removal of a C from the carboxyl end. α oxidization in peroxisome In humans we break down dietary phytanic acid (from dairy and some fish) Phytanic acid is converted to pristanic acid Phytanic Acid Aldehyde DH Alpha oxidation due to Methyl group on beta C Pristanic acid Beta oxidation can now occur Same as VLCFA Defects in α- oxidation lead to increase in phytanic acid that can lead to Refsum disease (autosomal recessive neurological disorder) ω-Oxidation of FA occurs in ER ω-C is the terminal methyl group Enzymes in ER membrane can oxidize this carbon ω-methyl group is oxidized to an OH The oxidization is carried out by a member of the cytochrome P450 (CYP) family of enzymes: CYP4A and CYP4F CYP enzymes are abundant in the liver and kidneys Role of Peroxisomal α and β oxidization and ωoxidization Peroxisomal α and β oxidization and microsomal ω- oxidization are not feedback regulated. Pathways function to decrease levels of waterinsoluble fatty acids or xenobiotic compounds that can become toxic to cells if stored at high levels Key concepts Key concepts: MCFA from diet are not stored but oxidized by liver and kidney Odd chain FA are oxidized first in the peroxisome VLCFA are oxidized first in the peroxisome Peroxisome performs alpha oxidization All oxidation in peroxisome generates hydrogen dioxide during first step of beta oxidization The ER does omega oxidization – minor unless needed due to deficiency in beta oxidization