Síntesis de ácidos grasos

Transcripción

1 Síntesis de ácidos grasos Las vías de síntesis y degradación son distintas Es similar a lo que ocurre entre glicolisis y gluneogénesis, síntesis y degradación de glicógeno Existen 4 diferencias esenciales entre la vía de síntesis y degradación de ácidos grasos

2 Las Diferencias Durante la síntesis los intermediarios estan unidos a un grupo -SH de una Proteína Portadora de Acilos (acyl carrier proteins ACP) comparado al grupo SH del CoA durante la degradación La Biosíntesis ocurre en el citosol; mientras que la degradación en la mitocondria Actividades Enzimáticas en la síntesis están en un polipéptido Biosintesis usa NADPH/NADP + ; degradación usa FADH 2 /FAD + ; NADH/NAD +

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4 Activation by Malonyl-CoA Acetate Units are Activated for Transfer in Fatty Acid Synthesis by Malonyl-CoA Fatty acids are built from 2-C units - acetyl-coa Acetate units are activated for transfer by conversion to malonyl-coa Decarboxylation of malonyl-coa and reducing power of NADPH drive chain growth Chain grows to 16-carbons Other enzymes add double bonds and more Cs

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6 Challenge: Ac-CoA in Cytosol What are the sources? Amino acid degradation produces cytosolic acetyl-coa FA oxidation produces mitochondrial acetyl-coa Glycolysis yields cytosolic pyruvate which is converted to acetyl-coa in mitochondria Citrate-malate-pyruvate shuttle provides cytosolic acetate units and reducing equivalents for fatty acid synthesis

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9 Acetyl-CoA Carboxylase The "ACC enzyme" commits acetate to fatty acid synthesis Carboxylation of acetyl-coa to form malonyl- CoA is the irreversible, committed step in fatty acid biosynthesis ACC uses bicarbonate and ATP (AND biotin!) E.coli enzyme has three subunits Animal enzyme is one polypeptide with all three functions - biotin carboxyl carrier, biotin carboxylase and transcarboxylase

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12 Acetyl-CoA Carboxylase II ACC forms long, active filamentous polymers from inactive protomers As a committed step, ACC is carefully regulated Palmitoyl-CoA (product) favors monomers Citrate favors the active polymeric form Phosphorylation modulates citrate activation and palmitoyl-coa inhibition

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18 Further Processing of FAs Additional elongation - in mitochondria and ER Introduction of cis double bonds - do you need O 2 or not? E.coli add double bonds while the site of attack is still near something functional (the thioester) Eukaryotes add double bond to middle of the chain - and need power of O 2 to do it Polyunsaturated FAs - plants vs animals...

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31 Biosíntesis de Colesterol El hígado es el lugar de sítesis más importante La tercera reacción, catalizada por- HMG- CoA reductasa es la etapa limitante en la biosíntesis de colesterol. HMG-CoA reductasa es el blanco de acción de las drogas que disminuyen los niveles de colesterol en la sangre.

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35 Regulation of HMG-CoA Reductase As rate-limiting step, it is the principal site of regulation in cholesterol synthesis 1) Phosphorylation by camp-dependent kinases inactivates the reductase 2) Degradation of HMG-CoA reductase - half-life is 3 hrs and depends on cholesterol level 3) Gene expression (mrna production) is controlled by cholesterol levels

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38 Cholesterol from Squalene At the endoplasmic reticulum membrane Squalene monooxygenase converts squalene to squalene-2,3-epoxide A cyclase converts the epoxide to lanosterol Though lanosterol looks like cholesterol, 20 more steps are required to form cholesterol! All at/in the endoplasmic reticulum membrane

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40 Inhibiting Cholesterol Synthesis Merck and the Lovastatin story... HMG-CoA reductase is the key - the ratelimiting step in cholesterol biosynthesis Lovastatin (mevinolin) blocks HMG-CoA reductase and prevents synthesis of cholesterol Lovastatin is an (inactive) lactone In the body, the lactone is hydrolyzed to mevinolinic acid, a competitive (TSA!) inhibitor of the reductase, K i = 0.6 nm!

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