Unit 6 - Fatty Acid Synthesis and Eicosanoids Flashcards
where and how does lipogenesis occur? what is the overall product?
synthesis of fats from glucose
- happens in liver, when glucose –> pyruvate –> citrate
- unlike ACoA, citrate can exit mitochondria to cytosol
- in cytosol, becomes ACoA –> mCoA (2 C donor for FAS)
- product is palmitic acid (C16)
what are the enzymes to convert pyruvate to OAA or ACoA? which one functions in lipogenesis and why? what happens after this?
to OAA: pyruvate carboxylase
-functions in lipogenesis b/c ACoA cannot cross mitochondrial double membrane
to ACoA: pyruvate dehydrogenase
then OAA and ACoA used to make citrate in mitochondria, which crosses double membrane to cytosol
what does citrate lyase do and where? why is this so?
converts citrate to OAA and ACoA in the cytosol
-pyruvate dehydrogenase is only in mitochondria, and ACoA can’t cross mitochondrial double membrane
since NADPH is required for FA synthesis, where does this come from? (2 places)
recycling of OAA
- OAA reduced by NADH dependent cytosolic malate dehydrogenase to malate
- malate converted by NADP+-dependent malic enzyme to oxidize and decarboxylate to pyruvate, making NADPH in the process
pentose-phsophate pathway
what are the 2 enzymes needed for FA synthesis? which one is the rate-limiting step?
- ACC (acetyl CoA carboxylase); rate limiting
2. FAS (fatty acid synthase)
what are the 5 basic steps in FA synthesis? which step is rate-controlling?
- activation (rate-controlling)
- condensation (beta-keto C=O)
- reduction (C-OH)
- dehydration (C=C)
- reduction (C-C)
last 4 are done by one enzyme
what happens when OAA increases in the matrix?
condenses with ACoA to make citrate
-reduced ACoA activates pyruvate dehydrogenase (to make more ACoA) and inhibits pyruvate carboxylase (to make less OAA)
what is acetyl CoA carboxylase and what does it do? what is its cofactor?
ACoA + CO2 + ATP –> mCoA + ADP + Pi
- biotin cofactor is linked to epsilon amino group of lys in ACC
- attachment of CO2 to biotin needs ATP hydrolysis
- carboxyl group added to ACoA to convert to mCoA
what is fatty acid synthase? what does it do? what is it comprised of?
catalyzes last 4 steps of FA synthesis
- homodimer, and each subunit has 7 catalytic activities and an acyl carrier PRO segment in a single polypeptide chains (so 7 reactions, 1 enzyme)
- adds 2 carbon units from mCoA to growing FA chain, with the final product being palmitate
what is the phosphopantethenyl residue of FA synthase?
covalently attached to serine on acyl carrier PRO (ACP) subunit
- 2 subunits associate head-to-tail so that phospho-pantetheinyl sulfhydryl group on one subunit is close to cysteinyl sulfhydryl group on other subunit
- SH group reacts with mCoA to form a thioester bond
what is the product after one round of FAS? what happens to it now?
a 4 carbon fatty acyl chain
-transferred from ACP phospho-pantetheinyl sulfhydryl group to cysteinyl phosphopantetheinyl sulfhydryl group to allow binding of next malonyl group and repetition of steps 2-5 until palmitate (C16) made
what happens after palmitate is made?
palmitate is released from FAS and activated to palmitoyl-CoA
-PCoA (and other long chain activated CoAs, saturated and unsaturated) elongated 2 C at a time by ER elongases, after being attached to Coenzyme A
what is the major elongation that occurs in human bodies?
palmityl CoA to stearyl CoA (C16 to C18)
-longer FA chains formed in brain (20-24)
what is FA desaturation? what does it need?
oxidation of FA to make cis double bonds
- makes lipids with increasing structural and functional complexity with distinct biological roles
- needs desaturases in ER that need O2, NADH, and cytochrome b5 (carries electrons thru ER)
are desaturases regulated?
highly regulated in response to diet
- during starvation, desaturase decreases sharply, then increases upon re-feeding CHO
- when large amounts of unsaturated fats are eaten, activity decreases
what are the 3 distinct desaturases in humans? how are they distinguished? what is the most active, and the FA it makes?
delta 9, 6, and 5 desaturases
- distinguished by position of DB insertion within FA chain
- d9 is most active, making 16:1 d9 (palmitoleic) and 18:1 d9 (oleic), both MUFAs
what are PUFAs needed for? how are they obtained?
omega-3s and omega-6s needed for eicosanoid synthesis, and obtained from diet
- linoleic and linolenic from plant oils
- they are all essential
what is arachidonic acid important for? is it an essential FA?
part of certain membrane lipids, and a precursor of eicosanoid signaling molecules
- made from linoleic acid (18:2 –> 20:4)
- even though AA is omega-6, it’s not essential if linoleic acid is present, but if no linoleic, then AA is essential
what is arachidonic acid used as a substrate for?
3 major eicosanoids in 3 different pathways
- lipoxygenase –> leukotrienes, HETEs, lipoxins
- cyclo-oxygenases –> prostaglandins, prostacyclins, thromboxanes
- cytP450 –> epoxides
a given type of cell usually only has enzymes for one of these pathways
what are eicosanoids?
ubiquitous C20 compounds with hromone-like effects on cell physiology
- unstable with short biological half-life
- made in situ and local mediators, involved in inflammatory response, smooth muscle contraction, bronchoconstriction, or bronchodilation
what kind of cell has both cyclic and linear (lipoxygenase) pathways?
platelets
-so can make cyclic (prostaglandins, thromboxanes, prostacyclins) and linear (leukotrienes, HETEs, lipoxins)
what does the cyclooxygenase (cyclic) pathway make? what is it inhibited by?
prostaglandins, prostacyclins, and thromboxanes
-inhibited by aspirin and other NSAIDs by acting on COX (which converts AA to PGH2)
what is the difference between COX-1 and COX-2
1: constitutive form in all tissues
2: inducible form regulated by variety of cytokines and growth factors
- increased in response to inflammation
what arachidonic acid product is involved in inflammatory pain? smooth muscle contractions of lungs?
inflammation: prostaglandins
lungs: leukotrienes
what does the lipoxygenase pathway make?
leukotrienes, HETEs (hydroxyeicosatetraenoic acids), and lipoxins from a common intermediate HPETE
what does the cyt P450 pathway make?
epoxides that make diHETE or HETE
how does aspirin work in cyclo-oxygenase path? how about acetaminophen and ibuprofen?
aspirin: irreversibly inhibits by acetylating COX-1/2
-attach to serine of active COX, and release salicylate
acetaminophen and ibuprofen: reversibly inhibit COX-1/2
