Lipids Flashcards

Question

Explain the diversity of membrane lipids

Answer 1

Enormous diversity of membrane lipids due the the various combination of hydrophilic head groups coupled to the various fatty acids

Answer 2

Lipids in bilayers are amphipathic meaning they have a polar part and a hydrophobic part. The hydrophobic part (fatty acids) interact with each other and the hydrophilic parts interact with exterior and cytoplasm

Answer 3

FIGURE 11-3 FLUID MOSAIC MODEL FOR MEMBRANE STRUCTURE. Interior fatty acyl chains form a fluid, hydrophobic region. Integral proteins float in this sea of lipid. Both proteins and lipids are free to move laterally in the plane of the bilayer, but movement of from one leaflet of the bilayer to the other is restricted.

Answer 4

Fatty acids have very hydrophobic alkyl chains, which are surrounded by highly ordered water molecules. Second law of thermodynamics says that entropy of an isolated system not in equilibrium will tend to increase over time, i. e. will become more random…ordering of water molecules goes against this, therefore, thermodynamically unfavorable.

Answer 5

Each lipid molecule forces surrounding H2O molecules to become highly ordered, therefore, **entropy is reduced**

Answer 6

Only the lipid portions at the edge of the cluster force the ordering of water. Fewer H₂O molecules are ordered, and **entropy is increased**

Answer 7

All hydrophobic groups are sequestered from water; ordered shell of H₂O molecules minimised, and **entropy is further increased** over clusters of lipids or dispersed lipids

Answer 8

The common glycerophospholipids are _diacylglycerols_ linked to head-group alcohols through a phosphodiester bond. _Phosphatidic acid_ is the parent compound. Each derivative is named for the head-group alcohol (X), with the prefix "phosphatidyl-.” No triacylglyerides in membrane. Instead, have phospholipids that are amphipathic (hydrophobic and hydrophilic)

Answer 9

Each derivative is named for the head-group alcohol (X), with the prefix "phosphatidyl-.”

Answer 10

* Some lipids are signaling molecules. Some drugs block the production of these signaling lipids. * Some are slow acting, steroid hormones that effect gene expression by activating nuclear receptors – testosterone, estrogen, vit. A, E, D. * Some are fast acting, that bind membrane receptors - prostaglandins, leukotrienes.

Answer 11

Steriods synthesized from cholesterol. Signalling molecules Testosterone - male sex hormone. Estradiol - female sex hormone. Cortisol and aldosterone synthesized in adrenal cortex; regulate glucose metabolism and salt excretion, respectively. Prednisolone and prednisone are synthetic anti-inflammatory agents.

Answer 12

Cyclooxygenase (COX), officially known as prostaglandin-endoperoxide synthase (PTGS), is an enzyme that is responsible for formation of prostanoids, including **prostaglandins (COX-2)** such as prostacyclin and **thromboxane (COX-1)**. The abbreviation "COX" is more often encountered in medicine. In genetics, the "PTGS" symbol is officially used for the prostaglandin-endoperoxide synthase (cyclooxygenase) family of genes and proteins, because the stem "COX" was already used for the cytochrome c oxidase family of genes and proteins. Pharmacological inhibition of COX can provide relief from the symptoms of inflammation and pain. Non-steroidal anti-inflammatory drugs (NSAID), such as aspirin and ibuprofen, exert their effects through inhibition of COX. In terms of their molecular biology, COX-1 and COX-2 are of similar molecular weight, approximately 70 and 72 kDa, respectively, and having 65% amino acid sequence homology and near-identical catalytic sites. The most significant difference between the isoenzymes, which allows for selective inhibition, is the substitution of isoleucine at position 523 in COX-1 with valine in COX-2. The smaller Val523 residue in COX-2 allows access to a hydrophobic side-pocket in the enzyme (which Ile523 sterically hinders). Drug molecules, such as DuP-697 and the coxibs derived from it, bind to this alternative site and are considered to be selective inhibitors of COX-2.

Answer 13

Nonsteroidal anti-inflammatory drugs (NSAIDs) like aspirin and ibuprofen block formation of prostaglandins and thromboxanes from arachidonate by inhibiting the enzyme cyclooxygenase (COX). Block both COX-1 and COX-2

Answer 14

COX converts _arachidonate_ to _prostaglandins_ and _thromboxanes_, and is inhibited by _NSAIDs_ such as _aspirin_.

Answer 15

COX has a cyclooxgenase activity and a peroxidase activity, the cyclooxgenase activity is inhibited by NSAIDs.

Answer 16

A Ser residue is irreversibly acetylated by the acetyl group of aspirin

Answer 17

R-CH(CH₃)COO^-

Answer 18

A lipid-based signaling factor which increases platelet aggregation and forms a clot…stops bleeding. However, thromboxane increases blood clots that block blood flow and cause heart attack or stroke, therefore inhibiting it decreases cardiovascular disease. COX-1 is an enzyme involved in the production of thromboxane

Answer 19

Aspirin (acetylsalicylic acid) acetylates COX-1 and -2 and **inactivates them**. **Blocks production of** a lipid-based signaling factor called **thromboxane (COX-1)**, which increases platelet aggregation and forms a clot…stops bleeding. However, **thromboxane increases blood clots that block blood flow and cause heart attack or stroke**, therefore inhibiting it decreases cardiovascular disease.

Answer 20

COX-1 produces lipids products that protect stomach lining (inhibition causes bleeding), and produces **thromboxane**, which increases blood platelet aggrigation. COX-2 produces lipid products that mediate pain and inflammation, also produces **prostacyclin**, a prostaglandin that prevents platelet aggregation.

Answer 21

Inhibition of COX-2 alone reduces the body’s production of prostacyclin, a prostaglandin that prevents platelet aggregation and alters the ratio of prostacyclin to thromboxane which is made by COX-1. Therefore, it increases the risk of cardiovascular disease.

Answer 22

* Omega-3 fatty acids-polyunsaturated fatty acids with double bond in the ω-3 position. * Body cannot synthesize - α-linolenic [18:3 (∆^9,12,15)] - essential FA. * Omega-6 FAs (linoleic acid) are converted to arachidonic acid which is converted to pro-inflammatory agents called prostaglandins, eicosanoids, and leukotrienes. * **Omega-3’s are converted at a slower rate to arachidonic acid** [20:4 (∆^5,8,11,14)], therefore increasing ω3/ω6 ratio, **reduces inflammation**.

Answer 23

Cholesterol is a structural component of membranes and precursor for hormones and bile acids

Answer 24

C-8 and C-12 of arachidonate are in five-membered ring

Answer 25

C-8 and C-12 are in 7 member ring with 2 oxygens

Answer 26

series of three conjugated double bonds

Answer 27

Like glucose, fats they are metabolized to CO₂ and H₂O, but since lower oxidation state, oxidative metabolism of fats yields over twice the energy/dry weight as do carbohydrates or proteins. Because fats are nonpolar, they are stored in an anhydrous state, whereas glycogen, the storage form of glucose, is polar and stored in a form that contains twice its weight in water. **Hence, fats provide six times the metabolic energy of an equal weight of hydrated glycogen.**

Answer 28

Lipids are insoluble while lipases are soluble, so digestion takes place at the lipid-water interface

Answer 29

Lipids are not soluble and lipases are, so **digestion takes place at the lipid-water interface**. **Rate of lipid digestion depends on the surface area of the interface.**

Answer 30

Bile acids are secreted into the small intestine where they increase the lipid-water surface area due to their detergent activities that cause the formation of lipid micelles (further reading): Bile acids are steroid acids found predominantly in the bile of mammals and other vertebrates. Different molecular forms of bile acids can be synthesized in the liver by different species. Bile acids are conjugated with taurine or glycine in the liver, forming bile salts. Primary bile acids are those synthesized by the liver. Secondary bile acids result from bacterial actions in the colon. In humans, taurocholic acid and glycocholic acid (**derivatives of cholic acid**) and taurochenodeoxycholic acid and glycochenodeoxycholic acid (derivatives of chenodeoxycholic acid) are the major bile salts in bile and are roughly equal in concentration. Bile acids comprise about 80% of the organic compounds in bile (others are phospholipids and cholesterol). An increased secretion of bile acids produces an increase in bile flow. The main function of bile acids is to facilitate the formation of micelles, which promotes digestion and absorption of dietary fat, but they are increasingly being shown to have hormonal actions throughout the body.

Answer 31

Cholic acid is a primary bile acid that is insoluble in water (soluble in alcohol and acetic acid), it is a white crystalline substance. Salts of cholic acid are called cholates. Cholic acid, along with chenodeoxycholic acid, is one of the two major bile acids produced by the liver, where it is synthesized from cholesterol. Cyclopentanoperhydrophenanthrene ring structure

Answer 32

Sterane (cyclopentanoperhydrophenanthrenes or cyclopentane perhydro phenanthrene) compounds, also known as are a class of 4-cyclic compounds derived from steroids or sterols via diagenetic and catagenetic degradation and saturation. Steranes have an androstane skeleton with a side chain at carbon C-17. The sterane structure constitutes the core of all sterols.

Answer 33

Pancreatic lipase catalyzes the sequential hydrolysis of triacylglycerols at their 1 and 3 positions to generate free fatty acids and 2 monoglyceride

Answer 34

pancreatic phospholipase A₂ cleaves C2 fatty acid of phospholipids to yield lysophospholipids, which are detergents due to their amphipathic nature. Hence, they emulsify fat, like bile acids.

Answer 35

Triacylglycerides are degraded into free fatty acids and glycerol by lipases. *Pancreatic lipase* catalyzes the sequential hydrolysis of triacylglycerols at their 1 and 3 positions to generate free fatty acids and 2 monoglyceride

Answer 36

Phospholipids are also degraded by pancreatic phospholipase A₂, which cleaves C2 fatty acid to yield lysophospholipids, which are detergents due to their amphipathic nature. Hence, they emulsify fat, like bile acids.

Answer 37

The term lysophospholipid (LPL) refers to any phospholipid that is missing one of its two O-acyl chains. Thus, LPLs have a free alcohol in either the sn-1 or the sn-2 position. The prefix 'lyso-' comes from the fact that lysophospholipids were originally found to be hemolytic, however it is now used to refer generally to phospholipids missing an acyl chain. LPLs are usually the result of phospholipase A-type enzymatic activity on regular phospholipids such as phosphatidylcholine or phosphatidic acid, although they can also be generated by the acylation of glycerophospholipids or the phosphorylation of monoacylglycerols. Some LPLs serve important signaling functions such as lysophosphatidic acid

Answer 38

Bile salts emulsify dietary fats in the small intestine, forming mixed micelles Intestinal lipases degrade triacylglycerols Fatty acids and other breakdown products are taken up by the intestinal mucosa and converted into triacylglycerols Triacylglycerols are incorporated, with cholesterol and apolipoproteins into chylomicrons Chylomicrons move through lymphatic system and bloodstream to tissues Lipoprotein lipase, activated by apoC-II in the capilary, converts triacylglycerols to fatty acids and glycerol Fatty acids ender cells, where they are oxidised as fuel or reesterified for storage

Answer 39

The surface is a layer of phospholipids. Triacylglycerols inside (yellow) make up more than 80% of the mass. Several apolipoproteins are on surface (B-48, C-III, C-II) and signal uptake of chylomicrons

Answer 40

Chylomicrons have a single phospholipid layer, and the inside is a hydrophobic region dominated by triacylglycerols. Vesicles have a lipid bilayer and so the inside is cytoplasmic or hydrophillic

Answer 41

When low levels of glucose in the blood trigger the release of glucagon, (1) the hormone binds its receptor in the adipocyte membrane and thus (2) stimulates adenylyl cyclase, via a G protein, to produce cAMP. This activates PKA, which phosphorylates (3) the hormone-sensitive lipase and (4) perilipin molecules on the surface of the lipid droplet. Phosphorylation of perilipin permits hormone-sensitive lipase access to the surface of the lipid droplet, where (5) it hydrolyzes triacylglycerols to free fatty acids. (6) Fatty acids leave the adipocyte, bind serum albumin in the blood, and are carried in the blood; they are released from the albumin and (7) enter a myocyte via a specific fatty acid transporter. (8) In the myocyte, fatty acids are oxidized to CO₂, and the energy of oxidation is conserved in ATP, which fuels muscle contraction and other energy-requiring metabolism in the myocyte.

Answer 42

Serum albumin, often referred to simply as blood albumin, is an albumin (a type of globular protein) found in vertebrate blood. Serum albumin is produced by the liver, occurs dissolved in blood plasma and is the most abundant blood proteinin mammals. Albumin is essential for maintaining the oncotic pressure needed for proper distribution of body fluidsbetween blood vessels and body tissues; without albumin, the high pressure in the blood vessels would force more fluids out into the tissues. **It also acts as a plasma carrier by non-specifically binding several hydrophobic steroid hormones and as a transport protein for hemin and fatty acids**. Too much or too little circulating serum albumin may be harmful. Albumin in the urine usually denotes the presence of kidney disease. Occasionally albumin appears in the urine of normal persons following long standing (postural albuminuria).

Answer 43

Perilipin is a protein that coats lipid droplets in adipocytes, the fat-storing cells in adipose tissue. Perilipin acts as a protective coating from the body’s natural lipases, such as hormone-sensitive lipase, which break triacylglycerides into glycerol and free fatty acids for use in metabolism, a process called lipolysis. In humans, perilipin is expressed in three different isoforms, A, B, and C, and perilipin A is the most abundant protein associated with the adipocyte lipid droplets. Perilipin is hyperphosphorylated by PKA following β-adrenergic receptor activation. **Phosphorylated perilipin changes conformation, exposing the stored lipids to hormone-sensitive lipase-mediated lipolysis**. Although _PKA also phosphorylates hormone-sensitive lipase_, which can increase its activity, the more than 50-fold increase in fat mobilization (triggered by epinephrine) is primarily due to perilipin phosphorylation.

Answer 44

The main function of hormone-sensitive lipase (triglyceride lipase) is to mobilize the stored fats. **HSL functions to hydrolyze the first fatty acid from a triacylglycerol molecule, freeing a fatty acid and diglyceride**. It is also known as triglyceride lipase, while the enzyme that cleaves the second fatty acid in the triglyceride is known as diglyceride lipase, and the third enzyme that cleaves the final fatty acid is called monoglyceride lipase. Only the initial enzyme is affected by hormones, hence its hormone-sensitive lipase name. The diglyceride and monoglyceride enzymes are tens to hundreds of times faster, hence **HSL is the rate-limiting step in cleaving fatty acids from the triglyceride molecule.** Activated when phosphorylated by PKA

Answer 45

The PKA enzyme is also known as cAMP-dependent enzyme because it gets activated only if cAMP is present. Hormones such as glucagon and epinephrine begin the activation cascade (that triggers protein kinase A) by binding to a G protein-coupled receptor (GPCR) on the target cell. When a GPCR is activated by its extracellular ligand, a conformational change is induced in the receptor that is transmitted to an attached intracellular heterotrimeric G protein complex. The Gs alpha subunit of the stimulated G protein complex exchanges GDP for GTP and is released from the complex. The activated Gs alpha subunit binds to and activates an enzyme called adenylyl cyclase, which, in turn, catalyzes the conversion of ATP into cyclic adenosine monophosphate (cAMP) -- increasing cAMP levels. Four cAMP molecules are required to activate a single PKA enzyme. This is done by two cAMP molecules binding to each of the two regulatory subunits on a PKA enzyme causing the subunits to detach exposing the two (now activated) catalytic subunits. Next the catalytic subunits can go on to phosphorylate other proteins. Below is a list of the steps involved in PKA activation: 1. Cytosolic cAMP increases 2. Two cAMP molecules bind to each PKA regulatory subunit 3. The regulatory subunits move out of the active sites of the catalytic subunits and the R2C2 complex dissociates 4. The free catalytic subunits interact with proteins to phosphorylate Ser or Thr residues. Downregulation of protein kinase A occurs by a feedback mechanism: One of the substrates that are activated by the kinase is a phosphodiesterase, which quickly converts cAMP to AMP, thus reducing the amount of cAMP that can activate protein kinase A. Thus, PKA is controlled by cAMP. Also, the catalytic subunit itself can be down-regulated by phosphorylation.

Answer 46

The reaction takes place in the cytosolic side of the outer mitochondrial membrane

Answer 47

*fatty acyl-CoA synthetase* adds fatty acid to S-CoA in two steps using ATP, *inorganic pyrophosphatase* converts pyrophosphate (P₂O₇) into 2P_i ∆G'° for both steps of fatty acyl-CoA synthetase = -15 kJ/mol ∆G'° for inorganic pyrophosphatase = -19 kJ/mol

Answer 48

The two-step process by which a fatty acid is converted to fatty acyl-CoA by the enzyme *fatty acyl-CoA synthetase* is: The carboxylate ion is adenylylated by ATP forming fatty acyl-adenylate (AMP bound to the fatty acid) and PP_i (pyrophosphate, degraded to 2P_i by *inorganic pyrophosphatase*). Thiol group of CoA attacks the acyl-adenylate (a mixed anhydride), displacing AMP and forming the thioester fatty acyl-CoA.

Answer 49

After fatty acyl–carnitine is formed at the outer membrane or in the intermembrane space, it moves into the matrix by facilitated diffusion through the transporter in the inner membrane. In the matrix, the acyl group is transferred to mitochondrial coenzyme A, freeing carnitine to return to the intermembrane space through the same transporter. Acyltransferase I is inhibited by malonyl-CoA, the first intermediate in fatty acid synthesis. This inhibition prevents the simultaneous synthesis and degradation of fatty acids.

Answer 50

Fatty acyl–carnitine formed in outer mitochondrial membrane moves into the matrix by facilitated diffusion through the transporter. In matrix, the acyl group is transferred to mitochondrial coenzyme A, carnitine returns to the intermembrane space through the same transporter.

Answer 51

Acyltransferase I is inhibited by malonyl-CoA, the first intermediate in fatty acid synthesis. This inhibition prevents the simultaneous synthesis and degradation of fatty acids.

Answer 52

The carnitine-mediated entry process is the rate- limiting step for oxidation of fatty acids in mitochondria and is a regulation point. Once inside the mitochondrion, the fatty acyl–CoA is acted upon by a set of enzymes in the matrix.

Answer 53

Stage 1: Fatty acid is oxidized to acetyl-CoA. This process is called β-oxidation. Stage 2: Acetyl groups oxidized to CO₂ via the citric acid cycle. Stage 3: Electrons derived from the oxidations of stages 1 and 2 pass to O₂ via the respiratory chain, providing the energy for ATP synthesis by oxidative phosphorylation.

Answer 54

A double bond is formed between the α and β carbons in the fatty acyl-CoA by *acyl-CoA dehydrogenase*, transferring 2H⁺ and 2e^- to FAD, reducing it to FADH₂. FADH₂ enters the ETC.

Answer 55

The C=C double bond between carbons α and β is hydrated by *enoyl-CoA hydratase*, forming a β-hydroxy-acyl-CoA

Answer 56

The β-hydroxy acyl-CoA formed in step II is dehydrogenated, forming a β-ketoacyl-CoA, transferring 2 H⁺ and 2 e^- to NAD⁺, reducing it to NADH + H⁺. NADH enters the ETC.

Answer 57

C1 and C2 of the fatty-acyl-CoA, along with CoA, are cleaved from the rest of the fatty acid by *acyl-CoA acetyltransferase (thiolase)*, another molecule of CoA-SH is bound to the remaining fatty acid, the end effect is shortening the chain by 2 carbons. Acetyl-CoA enters the TCA cycle.

Answer 58

7 molecules of acetyl-CoA, two carbons are broken off every four steps. (number of carbons/2)

Answer 59

1 FADH₂ from step I, 1 NADH from step III, Acetyl-CoA and (*n*-2) Acyl-CoA from step IV.

Answer 60

C1 and C2 are the first to be removed, during step IV another molecule of CoA-SH enters and attatches to C3 of the chain. When a fatty acid is fully β-oxidised, the last two carbons (C19 and C20 of a 20-cabon fatty acid, for example) are the last to be removed as acetyl-CoA

Answer 61

The first three steps are similar to the reactions that converty succinate to oxaloacetate in the TCA cycle

Answer 62

1.5 ATP per FADH₂, 2.5 ATP per NADH

Answer 63

Palmitoyl-CoA is part of the carnitine shuttle system, which transports other fatty acyl-CoA molecules into the mitochondria for β-oxidation. 16-carbon fatty acyl-CoA

Answer 64

Lots of H₂O The oxidation of palmitoyl-CoA (C16 fatty acid) yields 23 H₂O molecules. H₂O comes from the reduction of O₂ to H₂O during electron transport. For some animals like gerbils and killer whales the oxidation of fatty acids is a significant source of dietary water. A striking example is the camel, whose hump is essentially a large hump of fat. Metabolism of fatty acids provides both needed water and energy during periods when drinking is not possible

Answer 65

Electrons reach Q through Complexes I (oxidation of NADH to NAD⁺) and II (oxidation of succinate to fumarate). The reduced Q (QH₂) serves as a mobile carrier of electrons and protons. It passes electrons to Complex III, which passes them to another mobile carrier, cytochrome c. Complex IV then transfers electrons from reduced cytochrome *c* to O₂. Electron flow through Complexes I, III, and IV is accompanied by proton flow from the matrix to the intermembrane space.

Answer 66

∆³, ∆²-enoyl-CoA isomerase converts β, γ *cis* bond to α, β *trans* bond Oleic acid, as oleoyl-CoA (∆⁹), is the example used here. Oxidation requires an additional enzyme, *∆³, ∆²-enoyl-CoA isomerase*, to reposition the double bond, converting the *cis* isomer to a *trans* isomer, a normal intermediate in *β* oxidation (enters *β*-oxidation II).

Answer 67

Besides being oxidized via the citric acid cycle, acetyl Co-A has another fate in liver mitochondria. In a process called **ketogenesis**, acetyl CoA is converted to acetoacetate or β-hydroxybutyrate. These compounds along with acetone are known as ketone bodies, even though β-hydroxybutyrate is not a ketone! Serve as important fuels for heart, skeletal muscle, kidney cortex and the brain during starvation. Not used by liver.

Answer 68

acetoacetate

Answer 69

D-*β*-hydroxybuterate

Answer 70

Ketone bodies are water soluble equivalents of short fatty acids. * Are synthesized in the mitochondrial matrix. * Acetone is not metabolized, rather “blown off” in lungs. * During ketosis, which accompanies untreated diabetes, more ketone bodies are produced than can be metabolized. * Ketosis also accompanies high protein-low carbohydrate diets, such as the Atkins or South Beach diets. * Because ketone bodies are acids, under extreme conditions, like untreated diabetes, high levels can lead to blood acidosis.

Answer 71

During ketosis, which accompanies untreated diabetes, more ketone bodies are produced than can be metabolized. * Ketosis also accompanies high protein-low carbohydrate diets, such as the Atkins or South Beach diets. * Because ketone bodies are acids, under extreme conditions, like untreated diabetes, high levels can lead to blood acidosis

Answer 72

1. Oxaloacetate is limiting because it is used for glucose in gluconeogenesis. 2. NADH levels are high, so PDC, isocitrate dehydrogenase and alpha ketoglutarate DeH are shut down. Conditions that promote gluconeogenesis (untreated diabetes, severely reduced food intake) slow the citric acid cycle (by drawing off oxaloacetate) and enhance the conversion of acetyl-CoA to acetoacetate. The released coenzyme A allows continued β oxidation of fatty acids (further reading) The acetyl-CoA produced by β-oxidation enters the citric acid cycle in the mitochondrion by combining with oxaloacetate to form citrate. This results in the complete combustion of the acetyl-CoA to CO₂ and water. This is the fate of acetyl-CoA wherever *β*-oxidation of fatty acids occurs, except under certain circumstances in the liver. In the liver oxaloacetate is wholly or partially diverted into the gluconeogenic pathway during fasting, starvation, a low carbohydrate diet, prolonged strenuous exercise, and in uncontrolled type 1 diabetes mellitus. Under these circumstances oxaloacetate is hydrogenated to malate which is then removed from the mitochondrion to be converted into glucose in the cytoplasm of the liver cells, from where it is released into the blood. In the liver, therefore, oxaloacetate is unavailable for condensation with acetyl-CoA when significant gluconeogenesis has been stimulated by low (or absent) insulin and high glucagon concentrations in the blood. **Under these circumstances acetyl-CoA is diverted to the formation of acetoacetate and β-hydroxybutyrate**. Acetoacetate, β-hydroxybutyrate, and their spontaneous breakdown product, acetone, are known as ketone bodies. The ketone bodies are released by the liver into the blood. All cells with mitochondria can take ketone bodies up from the blood and reconvert them into acetyl-CoA, which can then be used as fuel in their citric acid cycles, as no other tissue can divert its oxaloacetate into the gluconeogenic pathway in the way that the liver does this. Unlike free fatty acids, ketone bodies can cross the blood-brain barrier and are therefore available as fuel for the cells of the central nervous system, acting as a substitute for glucose, on which these cells normally survive. The occurrence of high levels of ketone bodies in the blood during starvation, a low carbohydrate diet, prolonged heavy exercise and uncontrolled type 1 diabetes mellitus is known as ketosis, and in its extreme form in out-of-control type 1 diabetes mellitus, as ketoacidosis.

Answer 73

Normally, ketone body formation is low. When acetyl-CoA accumulates (as in starvation or untreated diabetes), *thiolase* catalyzes the condensation of two acetyl-CoA molecules to acetoacetyl-CoA and then to HMG-CoA, the parent compound of the three ketone bodies. Ketone body formation occur in the matrix of liver mitochondria.

Answer 74

*β*-hydroxy-*β*-methylglutaryl-CoA (HMG-CoA)

Answer 75

Three acetyl groups connected to CoA-SH

Answer 76

Once inside target cell, the reaction that forms ketone bodies is reversed ## Footnote D-*β*-Hydroxy-butyrate from liver travels through blood to other tissues, where it is converted in three steps to acetyl-CoA.

Answer 77

*β*-ketoacyl-CoA transferase, which hydrolyses succinyl-CoA into succinate and CoA-SH. This is required to catabolise ketone bodies. It is missing in the liver because the liver makes ketone bodies for other organs that cannot recieve fatty acids directly to catabolise, such as the brain.

Answer 78

2 acetyl-CoA molecules

Answer 79

Oxidation in mitochondria, synthesis in cytosol.

Answer 80

The redox coenzyme for fatty acid synthesis is NADPH. Degradation uses NAD⁺ and FAD.

Answer 81

Intermediates in synthesis are linked to sulfydryl of an acyl- carrier protein (ACP). In breakdown attached to CoA.

Answer 82

Fatty acids are constructed by two-carbon units derived from acetyl CoA. Synthesis requires an ATP-dependent carboxylation of acetyl-CoA to form malonyl CoA followed by the exergonic decarboxylation of the malonyl group in a condensation reaction that adds the acetyl group. The elongation reactions are repeated until the growing chain reaches 16 carbons in length (palmitic acid). Other enzymes add double bonds or additional units.

Answer 83

palmitic acid

Answer 84

malonyl-CoA

Answer 85

Acetyl CoA Carboxylase (ACC) Biotin-dependent enzyme in ER, **catalyzes the first committed and a rate-controlling step of fatty acid synthesis**. Protomer (monomer) is inactive. Active form is 4-8 million Dalton polymer. cAMP inhibits through phosphorylation by PKA, whereas insulin stimulates ACC activity through dephosphorylation. Phosphorylation favors inactive monomer. Citrate activates and palmitoyl-CoA (the product of fatty acid synthesis) inhibits.

Answer 86

PKA phosphorylation causes shift from polymers (active) to protomers (inactive).

Answer 87

biotin carrier protein (gray); 2. biotin carboxylase, which activates CO₂ by attaching it to a nitrogen in the biotin ring in an ATP-dependent reaction. 3. transcarboxylase, which transfers activated CO₂ (shaded green) from biotin to acetyl-CoA, producing malonyl-CoA.

Answer 88

Bicarbonate (HCO₃^-)

Answer 89

Holds activated CO₂ and transfers it between catalytic regions of the *acetyl-CoA carboxylase* enzyme

Answer 90

Biotin carboxylase, which activates CO₂ by attaching it to a nitrogen in the biotin ring in an ATP-dependent reaction.

Answer 91

Transcarboxylase, which transfers activated CO₂ from biotin to acetyl-CoA, producing malonyl-CoA.

Answer 92

Fatty acid synthesis involves seven enzymatic reactions that are carried out in bacteria by seven unique enzymes. In yeast and animals all activities as well as ACP are found in one protein. The mammalian enzyme (shown) consists of two identical large polypeptide chains. It is a dimer. The mammalian enzyme likely evolved from fusion of the individual bacterial genes.

Answer 93

As process starts, acetyl (or longer acyl) group bound to *β*-ketoacyl-ACP synthase and malonyl bound via a thioester bond to acyl carrier protein, both are delivered to the protein complex by CoA-SH

Answer 94

malonyl/acetyl transferase

Answer 95

Ketoacyl ACP synthase condenses acyl group and two carbons derived from malonyl-CoA, with elimination of CO₂, extends chain by two carbons. ## Footnote The *β*-keto product of this condensation is then reduced in three more steps nearly identical to the reactions of *β*-oxidation, but in the reverse sequence.

Answer 96

the β-keto group is reduced to an alcohol with electrons coming from NADPH by β-ketoacyl-ACP-reductase. (**β-carbon is reduced!**)

Answer 97

elimination of H₂O by β-hydroxacyl-ACP dehydratase creates a double bond. NOTE THAT THE CHEMISTRY IS THE REVERSE (NEARLY) OF FATTY ACID BREAKDOWN.

Answer 98

Enoyl-ACP recductase reduces the double bond, again with NADPH, to form the corresponding saturated fatty acyl group

Answer 99

Translocation of growing fatty acid to Cys residue on β-ketoacyl-ACP synthase from acyl carrier protein (ACP), then addition of a new malonyl-CoA to acetyl carrier protein synthase to begin addition of another 2 carbons

Answer 100

The fatty acyl chain grows by two-carbon units donated by activated malonate, with loss of CO₂ at each step. The initial acetyl group is shaded yellow, C-1 and C-2 of malonate are shaded pink, and the carbon released as CO₂ is shaded green. After each two-carbon addition, reductions convert the growing chain to a saturated fatty acid of 4, 6, 8 carbons etc. until (16:0) (palmitate)

Answer 101

At the end of the chain, the fatty acid is grown from "highest" carbon number to lowest, or towards the carboxyl group. The original methyl of acetate is the methyl of palmiate.

Answer 102

The prosthetic group is 4′-phosphopantetheine, which is covalently attached to the hydroxyl group of a Ser residue in ACP. Phosphopantetheine contains the B vitamin pantothenic acid, also found in the coenzyme A. SH group is the site of entry of malonyl groups during fatty acid synthesis

Answer 103

palmitate, a C₁₆ saturated fatty acid

Answer 104

Fatty acid elongation system in smooth ER extends by two carbons. Different enzymes but same process as fatty acid synthase except that ACP is replaced by acetyl-CoA. Still requires malonyl-CoA, followed by reduction, dehydration and reduction. Two rounds to make 20 carbon fatty acid from palmitate.

Answer 105

First, need to generate malonyl-CoA from acetyl-CoA, one for each two carbons you want to add. Requires 1 acetyl-CoA, 1 HCO₃, 1 ATP per malonyl-CoA produced. Second, you need to condense and reduce with fatty acid synthase. Requires 1 acetyl-CoA to prime the chain; then 1 malonyl-CoA, 2 NADPH + 2H⁺ per two cabons extended. To make palmitate, you need seven cycles on fatty acid synthase (7 cycles = 14 carbons added plus the 2 cabon primer = C₁₆ fatty acid), so total 8 acetyl-CoA, 7 ATP, 14 NADPH, 14 H⁺ gets you one palmitate

Answer 106

Chemical energy in two forms is required: group transferring potential of ATP and the reducing power of NADPH

Answer 107

The acetyl-CoA used for fatty acid synthesis is largely coming from pyruvate after decarboxylation by PDC, not *β*-oxidation, since the latter is reciprocally regulated and not active while fat stores are being built.

Answer 108

The pentose phosphate pathway

Answer 109

Acetyl groups pass out of the mitochondrion as citrate. *Citrate lyase* produces acetyl-CoA for fatty acid synthesis. Oxaloacetate is reduced to malate. Malate is oxidised by malic enzyme to generate cytosolic NADPH.

Answer 110

Acetyl-CoA carboxylase is the rate limiting enzyme of fatty acid synthesis. Both allosteric regulation and hormone-dependent covalent modification influence the flow of precursors into malonyl-CoA.

Answer 111

glucagon and epinephrine trigger phosphorylation/inactivation of *acetyl-CoA carboxylase* Palmitoyl-CoA (part of carnitine shuttle system, later stage product of fatty acid synthesis) inhibits *acetyl-CoA carboxylase*

Answer 112

insulin triggers activation of *citrate lyase*, which produces acetyl-CoA, and citrate triggers activation of *acetyl-CoA carboxylase*, which produces malonyl-CoA from acetyl-CoA

Lipids Flashcards

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