Unit 6 - Fatty Acid Synthesis and Eicosanoids Flashcards

1
Q

where and how does lipogenesis occur? what is the overall product?

A

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)
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2
Q

what are the enzymes to convert pyruvate to OAA or ACoA? which one functions in lipogenesis and why? what happens after this?

A

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

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3
Q

what does citrate lyase do and where? why is this so?

A

converts citrate to OAA and ACoA in the cytosol

-pyruvate dehydrogenase is only in mitochondria, and ACoA can’t cross mitochondrial double membrane

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4
Q

since NADPH is required for FA synthesis, where does this come from? (2 places)

A

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

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5
Q

what are the 2 enzymes needed for FA synthesis? which one is the rate-limiting step?

A
  1. ACC (acetyl CoA carboxylase); rate limiting

2. FAS (fatty acid synthase)

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6
Q

what are the 5 basic steps in FA synthesis? which step is rate-controlling?

A
  1. activation (rate-controlling)
  2. condensation (beta-keto C=O)
  3. reduction (C-OH)
  4. dehydration (C=C)
  5. reduction (C-C)

last 4 are done by one enzyme

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7
Q

what happens when OAA increases in the matrix?

A

condenses with ACoA to make citrate

-reduced ACoA activates pyruvate dehydrogenase (to make more ACoA) and inhibits pyruvate carboxylase (to make less OAA)

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8
Q

what is acetyl CoA carboxylase and what does it do? what is its cofactor?

A

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
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9
Q

what is fatty acid synthase? what does it do? what is it comprised of?

A

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
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10
Q

what is the phosphopantethenyl residue of FA synthase?

A

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
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11
Q

what is the product after one round of FAS? what happens to it now?

A

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

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12
Q

what happens after palmitate is made?

A

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

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13
Q

what is the major elongation that occurs in human bodies?

A

palmityl CoA to stearyl CoA (C16 to C18)

-longer FA chains formed in brain (20-24)

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14
Q

what is FA desaturation? what does it need?

A

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)
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15
Q

are desaturases regulated?

A

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
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16
Q

what are the 3 distinct desaturases in humans? how are they distinguished? what is the most active, and the FA it makes?

A

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
17
Q

what are PUFAs needed for? how are they obtained?

A

omega-3s and omega-6s needed for eicosanoid synthesis, and obtained from diet

  • linoleic and linolenic from plant oils
  • they are all essential
18
Q

what is arachidonic acid important for? is it an essential FA?

A

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
19
Q

what is arachidonic acid used as a substrate for?

A

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

20
Q

what are eicosanoids?

A

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
21
Q

what kind of cell has both cyclic and linear (lipoxygenase) pathways?

A

platelets

-so can make cyclic (prostaglandins, thromboxanes, prostacyclins) and linear (leukotrienes, HETEs, lipoxins)

22
Q

what does the cyclooxygenase (cyclic) pathway make? what is it inhibited by?

A

prostaglandins, prostacyclins, and thromboxanes

-inhibited by aspirin and other NSAIDs by acting on COX (which converts AA to PGH2)

23
Q

what is the difference between COX-1 and COX-2

A

1: constitutive form in all tissues
2: inducible form regulated by variety of cytokines and growth factors
- increased in response to inflammation

24
Q

what arachidonic acid product is involved in inflammatory pain? smooth muscle contractions of lungs?

A

inflammation: prostaglandins
lungs: leukotrienes

25
Q

what does the lipoxygenase pathway make?

A

leukotrienes, HETEs (hydroxyeicosatetraenoic acids), and lipoxins from a common intermediate HPETE

26
Q

what does the cyt P450 pathway make?

A

epoxides that make diHETE or HETE

27
Q

how does aspirin work in cyclo-oxygenase path? how about acetaminophen and ibuprofen?

A

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