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Fatty acid and lipid metabolism (FA are processed in 3 stages (activation…
Fatty acid and lipid metabolism
FA are processed in 3 stages
lipolysis
triacylglycerols are degraded FA and glycerol
lipases are stimulated by hormones: glucagon an epinephrine triggers the 7TM receptors to activate cyclase to produce cAMP
cAMP activates protein kinase A, which phosphorylated perilipin, a fat0droplet-associated protein, and adipose triglyceride lipase
free FA and glycerol are released into the blood
FA are not soluble in aqueous solution. --> the released FA bind to blood protein albumin which delivers them to tissues in need of fuel
glycerol is absorbed by liver and phosphorylated. it is oxidized to dihydroxyacetone phosphate, which is isomerized o glyceraldehyde 3-phosphate
activation of FA
FA separate from the albumin in the bloodstream and diffuse across the cell membrane with the assistance proteins
FA must be activated by reacting with coenz. A to form acyl CoA
this activation takes place on the outer MT membrane, where it is catalyzed by acyl CoA
he activation step is neccessary to move FA into MT matrix
acyl carnitine is shuttled across the inner MT membrane by a transporter
FA oxidation into acetyl CoA
FA are oxidized 2 C atoms at a time to acetyl CoA and releases high-energy electrons
a sequence of 4 reactions: oxidation by FAD, hydration, oxidation by NAD+, thiolysis by coenzyme A
products of beta oxidation: FADH2, NADH, acetyl CoA
the acyl chain is shortened by 2C. this chain undergoes another cycle of oxidation starting at the oxidation by FAD
the complete oxidation of palmitate yields 106 molec. of ATP
the degradation of unsat. FA requires an isomerase
a reductase is requires to degrade polyunsat. FA
ketone bodies are another fuel source derived from fats
some acetyl CoA units are used to form an alternative fuel source called ketone bodies-acetonacetate, D-3-hydroxybutyrate and acetone
ketone bodies are not as E rich as Fa, but they are water soluble allowing for easy transportation
under starvation conditions, acetone maybe captured to synthesize glucose
the presence of ketone bodies in urine suggests that the body is using fat instead of sugar as a major source of fuel
ketone body synthesis takes place in the MT of the liver
FA synthesis
our diet meets our physiological need fro fats and lipids --> adult human being have little need for FA synthesis
FA synthesis is necessary during embryonic development and during in mammary glands
too much FA synthesis in an alcohol's liver contributes to liver failure
3 stages
acetyl CoA is transferred from MT (where i is produced), to cytoplasm, the site of FA synthesis
the synthesis of palmitate requires 14 mole. of NADPH
FA synthesis begins in the cytoplasm with the activation of acetyl CoA in a 2 step reaction to matonyl CoA
the reaction intermediates are attached to an acyl carrier protein, which serves as the molecular foundation of FA being constructed. FA is synthesized 2C at a time, in a five elongation
condensation and reduction
in the condensation step, aceyl ACP and malonyl AcP react to form acetoacetyl ACP. CO2 is released
dehydration and another reduction
the final step is the reduction of the double bond with NADPH to produce buturyl ACP, which completes the first elongation cycle
the overall process of palmitate synthesis
the fatty acyl chain grows by 2C units donated by activated malonate, with loss of CO2 at each step. the initial acetyl group is shaded in yellow
routes of synthesis of other FA
palmitate (6:0) is the precursor of stearate and longer-chain sat FA, as well as palmitoleate ans oleate
mammals cannot convert oleate to linoleate, which are therefore required in the diet as essential FA
desaturation of FA requires a mixed-function oxidase
the double bond is introduced into the FA chain by an oxidative reaction catalyzed by fatty acetyl-CoA desaturase
acetyl CoA carboxylase is a key regulator of FA metabolism
acetyl CoA carboxylase1, catalyzed the commited step in FA synthesis, is switched off by phsphorelation and activated by dephosphorylation
citrate stimulate the carboxylase
the level of citrate is high when both acetyl CoA and ATP are abundant, signifying that raw mat. and E are available for FA synthesis
enz. acetyl CoA carboxylase exists as inactive isolated dimer. citrate t/o with the protein MIG12 facilitates the polymerixation of the dimers into active filament
mitochondrial malonyl CoA inhibits carnitine acyltransferase I, preventing the entry offatty acyl CoAs into the MT matrix
EtOH alters E metabolism in the liver
EtOH cannot be excreted and must be metabolized, primarily by the liver. one of the several pathways for the metabolism of EtOH consists of 2 steps
the consequences of increased NADH
EtOH consumption leads to an accumatation of NADH. this high conc. of NADH inhibits gluconeogenesis by preventing the oxidation of lactate to pyruvate, and lactate will accumulate. the consequences may be hypoglycemia (low cinc. of blood glucose) and lactate acidosis
synthesis from an activated alc.
EtOH amine is phosphorylated by ATP to form the precursor, phosphorylethanolamine, which reacts with CTP to form CDP-ethanolamine
spihgolipids are synthesized from ceramide
phosphatidic acid phsphatase is a key regulatory enz. in lipid metabolism
cholesterol is synthesized from acetyl CoA in 3 stages
synthesis of an activated isoprene, which is the key buiding block of cholesterol
condensation of squalene
cyclization of squalene and the tetracyclic products is converted into cholesterol
the synthesis of mevalonate initates the synthesis of cholesterol
squalene cyclizes to form cholesterol
squalene is first activated by conversion into squalene epoxide (2,3-oxidasqualene) in a reaction that uses O2 and NADPH
the regulation of cholesterol synthesis take place at several levels
lipoproteins transport cholesterol and triacylglycerols throughout the organism
low-density lipoproteins play a central role in cholesterol metabolism
the absecne of the LDL receptor leads to a familial hypercholesterolermia and antherosclerosis