chapter 16 biochem
Flux through lipid metabolizing pathways is regulated in response to three cellular demands:
(1) the changing energy needs of the cell; (2) the requirement for membrane components in rapidly dividing cells; and (3) the need to synthesize cholesterol derivatives (bile acids and steroids)
Enzymes that elongate palmitate exist in both
the mitochondria and as membrane components of the endoplasmic reticulum (ER)
The majority of acetyl-CoA used for fatty acid synthesis in the cytosol is derived from
the pyruvate dehydrogenase reaction, which takes place in the mitochondrial matrix
Lipoproteins
transport lipids throughout the body and function to control cholesterol homeostasis by regulating the input, recycling, and output of cholesterol on a daily basis.
The three other major lipoprotein classes are
very-low-density lipoproteins (VLDLs); intermediate-density lipoproteins (IDLs), also called VLDL remnants; and low-density lipo- proteins (LDLs).
In contrast, when glucose levels are high, AMP levels decrease and insulin signaling stimulates protein phosphatase 2C
which dephosphorylates AMPK. This leads to increased levels of dephosphorylated acetyl-CoA carboxylase in the active polymer conformation and elevated flux through the fatty acid synthesis pathway.
The most abundant bile acid in humans is cholate
which is further modified to make the more water-soluble bile salts taurocholate and glycocholate
In the first step of this reaction, fatty acyl-CoA synthetase
catalyzes the adenylation of a fatty acid to form the enzyme-bound intermediate fatty acyladenylate. This involves an attack by the carboxylate ion of the fatty acid on the α phosphate of ATP and release of pyrophosphate (PPi)
Serum lecithin-cholesterol acyltransferase
catalyzes the fatty acylation of cholesterol using a fatty acid from the C-2 carbon of phosphatidylcholine.
Sphingolipids, however, are derived from
ceramide
Figure 16.35 Flux through fatty acid synthesis and degradation pathways is controlled by three biochemical mechanisms:
citrate activation of acetyl-CoA carboxylase activity; inhibition of carnitine acyltransferase I activity by malonyl-CoA; and inhibition of acetyl-CoA carboxylase activity by fatty acyl-CoA
bile acids
Most of the bile acid is returned to the liver and reused; however, some of it is excreted as waste, which provides the only mechanism to rid the body of excess cholesterol
Synthesis of Fatty Acids and Triacylglycerols
16.2
Rapid metabolic regulation of acetyl-CoA carboxylase activity is mediated by
citrate and palmitoyl-CoA, which are allosteric regulators that bind to the enzyme and alter the equilibrium between polymerization (active) and depolymerization (inactive)
Arteriole plaques
contain large numbers of inflammatory cells, fibrous tissue, and cholesterol, which can lead to the formation of blood clots, restricting blood flow and resulting in cardiac arrest or stroke.
The biotin carrier domain of acetyl-CoA carboxylase
contains a biotin group covalently attached to a lysine residue
Delayed hormonal signaling by insulin
stimulates dephosphorylation and polymerization of acetyl-CoA carboxylase through activation of protein phosphatase 2A
The activity of AMPK is regulated by
AMP binding, which induces a conformational change in the protein, facilitating its phosphorylation at a regulatory threonine residue (Thr172).
The Citrate Shuttle Exports
Acetyl-CoA from Matrix to Cytosol
Beta oxidation results in electron transfer.
(1) Acyl-CoA dehydrogenase donates the electrons from the first fatty acid oxidation reaction to an enzyme-bound FAD molecule in the ETF. (2) This electron pair is then passed to an Fe-S center in the ETF-Q oxidoreductase enzyme. (3) The electrons are passed from the Fe-S center to coenzyme Q (Q), generating reduced coenzyme Q (QH2). (4) Reduced coenzyme Q is oxidized by complex III as part of the Q cycle
The carnitine transport cycle is a three-step process that translocates fatty acids across the inner mitochondrial membrane
(1) Carnitine acyltransferase I, which is inhibited by malonyl-CoA when fatty acid synthesis is favored, links carnitine to palmitoyl-CoA and releases CoA. (2) The carnitine-acylcarnitine translocase protein in the inner mitochondrial membrane exchanges palmitoylcarnitine for carnitine. (3) Carnitine acyltransferase II replaces carnitine with CoA.
the MAT domain in the fatty acid synthase complex also catalyzes this malonyl transfer reaction that generates malonyl-ACP. With substrates attached to both the KS domain (acetyl-S-Cys) and ACP (malonyl-ACP), the four-step reaction sequence is initiated
(1) condensa- tion catalyzed by KS; (2) reduction catalyzed by KR; (3) dehydration catalyzed by DH; and (4) reduction cata- lyzed by ER. In the final reaction of each synthesis cycle, the fully reduced product on ACP is translocated to the Cys residue on the KS subunit. The four-reaction synthesis cycle starts again when a new malonyl group is attached to ACP.
three regula- tory mechanisms prevent futile cycling between anabolic and catabolic pathways:
1. Excess acetyl-CoA in the mitochondria signals feedback inhibition of the citrate cycle under conditions of high energy charge, leading to citrate export to the cytosol where it stimulates depolymerization and activation of acetyl-CoA carboxylase activity. 2. High levels of malonyl-CoA inhibit carnitine acyltransferase I activity, which prevents mitochondrial import and degradation of fatty acyl-CoA molecules at the same time that fatty acid synthesis is favored. 3. When fatty acyl-CoA levels are high owing to dietary influx of fatty acids or decreased rates of very-low-density lipoprotein export (liver cells), acetyl-CoA carboxylase activity is inhibited by fatty acyl-CoA binding (stimulates enzyme depolymerization).
The combined reactions of the electron transport system and oxidative phosphorylation convert
31 NADH into ∼ 77.5 ATP (31 × ∼ 2.5 ATP), and the 15 FADH2 are converted into ∼ 22.5 ATP (15 × ∼ 1.5 ATP). When adding in the 8 ATP derived from 8 GTP generated in the citrate cycle, the total ATP yield from palmitoyl-CoA is 108 ATP. if one is calculating net ATP yields beginning with palmitate rather than beginning with palmitoyl-CoA, it is necessary to subtract 2 ATP equivalents required for the fatty acyl- CoA activation (106 ATP)
The Fatty Acid 𝛃-Oxidation Pathway in Mitochondria
A set of three enzymes called fatty acyl-CoA synthetases, which differ in their specificity for short-, medium-, and long-chain fatty acids, catalyze the formation of fatty acyl-CoA derivatives using an ATP-coupled reaction mechanism
The production of malonyl-CoA by acetyl-CoA carboxylase involves a two-step ATP-dependent reaction
that carries a carboxyl group from the biotin carboxylase active site to the carboxyltransferase active site using a carboxybiotin arm attached to the biotin carrier protein domain.
. Hypoglycin A is an unusual amino acid produced at 104-fold higher levels in unripe ackee fruit than in ripe ackee fruit.
After consumption of unripe ackee fruit, hypoglycin A is metabolized to a toxic intermediate called methylenecyclopropylacetic acid (MCPA), which is then is attached to CoA (MCPA-CoA). The MCPA-CoA inhibits liver mitochondrial acyl- CoA dehydrogenases and is the cause of Jamaican vomiting sickness. The symptoms of this dietary ailment are due to acute inhibition of several metabolic processes in liver cells, including reduced transport of long-chain fatty acids into the mitochondria and decreased fatty acid oxidation.
The mammalian fatty acid synthase complex has multiple functional domains
All five of the enzymatic functions (MAT, KS, KR, DH, ER) required for fatty acid synthesis, along with the two specialized domains (ACP, TE), are encoded on a single polypeptide of ∼ 2,500 amino acid residues in mammals. Domain abbreviations are listed.
AMPK is phosphorylated and activated by a variety of kinases, including
the LKB1 catalytic subunit of the AMPK kinase protein complex.
Metabolic and Hormonal Control of Fatty Acid Synthesis
Under conditions when the citrate cycle is inhibited by a high energy charge in the cell, the citrate shuttle provides a mechanism to transport excess acetyl units from the mitochondria to the cytosol for fatty acid synthesis. The oxidation of malate to pyruvate by malic enzyme generates NADPH, which is used in the fatty acid synthesis pathway
Biosynthetic pathways can convert liver cholesterol to cholesterol esters and bile acids.
Cholesterol esters can be stored in lipid droplets in the cell or exported to peripheral tissue as components of lipoprotein particles. Half of all cholesterol synthesized in the liver is converted to bile acids and secreted into the small intestine through the bile duct.
Auxiliary Pathways for Fatty Acid Oxidation
Degradation of the monounsaturated molecule oleoyl- CoA requires additional reactions to account for the C= C bond. Degradation of the odd-numbered C23 tricosanoyl-CoA generates 10 C2 acetyl-CoA molecules and one molecule of C3 propionyl-CoA. Three enzymatic steps are required to convert propionyl- CoA to the citrate cycle intermediate succinyl-CoA.
because mitochon- dria do not contain an "acetyl-CoA transporter,"
the acetate units are exported to the cytosol via the citrate shuttle.
An overview of the fatty acid synthesis cycle resulting in the production of palmitate is shown here.
Each cycle of the fatty acid synthase reactions elongates the chain by two carbons. Seven rounds of the cycle are required to produce C16 palmitate. Each round of the cycle uses 4 H+ and 4 e− (from NADPH and H+) and releases 1 CO2. In the final round of the cycle, the chain is not transferred to KS, but is instead hydrolyzed from ACP, releasing palmitate
What purposes do fatty acid oxidation and fatty acid synthesis serve in animals?
Fatty acid oxidation in mitochondria is responsible for providing energy to cells when glucose levels are low. Most humans store enough triacylglycerols in their adipose tissue to supply energy to the body for ∼ 3 months during starvation. Liver and adipose cells convert excess acetyl-CoA into fatty acids that can be stored or exported as triacylglycerols.
What are the net reactions of fatty acid degradation and synthesis for the typical C16 fatty acid palmitate?
Fatty acid oxidation: Palmitate + 7 NAD+ + 7 FAD + 8 CoA + 7 H2O + ATP → +8 Acetyl-CoA + 7 NADH + 7 FADH2 + AMP + 2 Pi + 7 H Fatty acid synthesis: 8 Acetyl-CoA + 7 ATP + 14 NADPH + 14 H+ → + Palmitate + 8 CoA + 7 ADP + 7 Pi + 14 NADP + 6 H2O
What are examples of fatty acid metabolism in everyday biochemistry?
Fatty acid oxidation: The kangaroo rat and the camel are two examples of animals that survive in desert environments for long periods of time without drinking water. They accomplish this by generating H2O internally through the complete oxidation of fatty acids. The kangaroo rat obtains fatty acids from oils in seeds, whereas camels store triacylglycerols in the adipose tissue of their humps. Fatty acid synthesis: A variety of foods are prominently advertised as "nonfat," even though they can contain a high calorie count coming from carbohydrates. Eating nonfat, high-calorie foods in excess of energy needs activates the fatty acid synthesis pathway, resulting in the conversion of acetyl-CoA to fatty acids, which are stored as triacylglycerols.
Synthesis of Triacylglycerol and Membrane Lipids
Fatty acids are the building blocks of triacylglycerols and also the hydrocarbon components of the most common membranelipids; namely, glycerophospholipids and sphingolipids
What are the key enzymes in fatty acid metabolism?
Fatty acyl-CoA synthetase: catalyzes the "priming" reaction in fatty acid metabolism, converting free fatty acids in the cytosol into fatty acyl-CoA using the energy available from ATP and pyrophosphate hydrolysis. Carnitine acyltransferase I catalyzes the com- mitment step in fatty acid oxidation, which links fatty acyl-CoA molecules to carnitine so they can be transported across the inner mitochondrial membrane. The activity of carnitine acyltransferase I is inhibited by malonyl-CoA, which is the product of the acetyl-CoA carboxylase reaction. Acetyl-CoA carboxylase catalyzes the commitment step in fatty acid synthesis using acetyl-CoA to form the C3 compound malonyl-CoA. The activity of acetyl-CoA carboxylase is regulated by both reversible phosphorylation and allosteric mechanisms. Fatty acid synthase, is responsible for catalyzing a series of reactions that sequentially adds C2 units to a growing fatty acid chain.
The carnitine transport cycle serves two important functions in regulating cellular metabolism
First, it provides a mechanism to control the flux of fatty acids either into the degradative pathway inside the mitochondrial matrix or toward the synthesis of triacylglycerols and membrane lipids in the cytosol. This regulatory decision is controlled by malonyl-CoA, which inhibits the activity of carnitine acyltransferase I and prevents the import of fatty acyl-CoA molecules into the mitochondria when lipid synthesis is favored. Second, the carnitine transport cycle functions to maintain separate pools of coenzyme A, which are involved in distinct processes. Cytosolic coenzyme A is used primarily for anabolic pathways, such as fatty acid synthesis, whereas mitochondrial coenzyme A is used for catabolic pathways, involving the degradation of pyruvate, fatty acids, and selected amino acids.
Acyl carrier protein functions as
the attachment site for the growing hydrocarbon chain within the fatty acid synthase complex.
Cholesterol Is Synthesized from Acetyl-CoA
Humans synthesize as much as 1 g of cholesterol per day and absorb ∼ 0.3 g per day from their diet.
Why is it dangerous to give insulin to an emergency room patient with severe ketoacidosis before first checking the patient's blood glucose levels?
If blood glucose levels are extremely high (hyperglycemic), then the ketoacidosis is probably due to the onset of diabetes, and administration of insulin is the proper treatment. However, if glucose levels are low (hypoglycemic), then the ketoacidosis is probably the result of dietary carbohydrate deficiency, and infusion with a high glucose solution is warranted. Giving insulin to a patient with ketoacidosis and hypoglycemia would decrease the patient's blood glucose levels even lower and lead to a life-threatening response.
Fatty acyl-CoA has either of two fates, depending on the energy charge of the cell.
If the energy charge is low, then fatty acyl-CoA is imported into the mitochondrial matrix by the carnitine transport cycle and degraded by the fatty acid oxidation reactions to yield acetyl-CoA, FADH2, and NADH. However, if the energy charge is high and fatty acid synthesis is favored, then mitochondrial import of fatty acyl-CoA is inhibited by the fatty acid precursor malonyl-CoA.
sterol regulatory element binding proteins (SREBPs).
In metabolism, is the control of cholesterol biosynthesis and lipogenesis (lipid synthesis)
Each round of fatty acid synthesis by the enzyme fatty acid synthase requires four conserved reactions.
In the first cycle of fatty acid synthesis, the acetyl group from acetyl-CoA is linked to two carbons derived from malonyl-CoA in a condensation reaction to form β-ketobutyryl-ACP. This moleculeis then converted to butyryl-ACP after a reduction, a dehydration, and another reduction. Butyryl-ACP serves as the protein-linked precursor for fatty acid chain extension in subsequent fatty acid synthesis cycles.
Apolipoprotein A-I (apoA-I) on the surface of HDL particles activates the enzyme lecithin-cholesterol acyltransferase.
Lecithin-cholesterol acyltransferase esterifies cholesterol in peripheral cell membranes with a fatty acid tail derived from phosphatidylcholine (lecithin). The esterified cholesterol is taken up into HDL particles and can be returned to the liver.
Cholesterol Metabolism and Cardiovascular Disease
Lipoprotein particles contain cholesterol esters and triacylglycerols stored inside a phospholipid monolayer studded with unesterified cholesterol. Human serum contains five major classes of lipoproteins, which vary in size and cargo components as listed in Table 16.2
𝛃-oxidation pathway
Once the electron-rich fatty acids are moved into the mitochondrial matrix, their value as high-energy metabolites is fully utilized to generate a substantial amount of ATP. This energy conversion process of fatty acid → ATP involves oxidation of fatty acids by sequential degradation of C2 units, resulting in the production of FADH2, NADH, and acetyl-CoA the sequential C2 cleavage reaction (thiolysis) occurs at the β carbon of the fatty acid
Two severe human metabolic diseases have been attributed to peroxisomal defects.
One is X-linked adrenoleukodystrophy (X-ALD), which is caused by a defect in a peroxisomal protein called adrenoleukodystrophy protein (ALDP). This protein belongs to the ATP binding cassette transporter superfamily and is encoded by the ABCD1 gene. The defect in adrenoleukodystrophy protein blocks peroxisomal import of saturated very-long-chain fatty acids, which accumulate in the cytosol before being exported to the blood, where they destroy neuronal cell myelin sheaths. Because the defective gene in X-ALD is encoded on the X chromosome, this often-fatal disease primarily affects boys, who suffer from progressive neuronal degeneration. Lorenzo's oil is a 4:1 mixture of glycerated oleic acid and erucic acid used as a homeopathic treatment for X-ALD. A second peroxisomal metabolic defect is Zellweger syndrome, which is caused by a complete lack of peroxisomes, resulting in death within the first year of birth. The rapid onset of lethal symptoms in infants with Zellweger syndrome attests to the critical role of peroxisomes in cellular metabolism.
palmitoyl-CoA is formed from palmitate in a reac- tion requiring the enzyme fatty acyl-CoA synthetase, which we described earlier in our discussion of fatty acid oxidation
Palmitoyl-CoA and malonyl-CoA are then linked through a condensation reaction catalyzed by one of several ER-localized fatty acyl elongation enzymes. The product of this reaction is then modified by the same three enzyme activities used in fatty acid synthesis; namely, a reduction, a dehydration, and a second reduction. In the final step, coenzyme A is removed from stearoyl-CoA to produce stearate.
Phosphatidylserine, phosphatidylethanolamine, and phosphatidylinositol are synthesized from phosphatidic acid.
Phosphorylation of phosphatidylinositol by phosphatidylinositol kinases generates phosphatidylinositol- 4,5-bisphosphate, which is an important membrane lipid involved in cell signaling. CMP = cytidine- 5′-monophosphate; CTP = cytidine triphosphate.
In addition to mitochondrial fatty acid oxidation, animal cells also degrade fatty acids in organelles called peroxisomes, which are found in almost all cell types.
Plants and eukaryotic microorganisms carry out fatty acid oxidation only in peroxisomes. The enzymatic steps in the peroxisomal fatty acid oxidation pathway are similar to β oxidation in mitochondria; however, utilization of ace- tyl-CoA, NADH, and FADH2 in energy conversion processes does not occur because citrate cycle and oxidative phosphorylation enzymes are lacking.
Figure 16.36 An overview of the cholesterol biosynthetic pathway is shown here.
Several intermediates in the cholesterol biosynthetic pathway are precursors for other biomolecules, such as chlorophylls, some lipid-soluble vitamins, and quinones. Importantly, cholesterol is the precursor to bile acids and steroid hormones. The four rings of cholesterol (C27) are labeled A, B, C, and D as shown.
the four stages of cholesterol biosynthesis
Stage 1: Generation of Mevalonate from Acetyl-CoA. In stage 1 of the cholesterol biosynthetic pathway, mevalonate (C6) is formed from three molecules of acetyl-CoA. The rate-limiting enzyme in the cholesterol biosynthetic pathway is HMG-CoA reductase, which is the target of statin drugs used to treat cardiovascular disease. Stage 2: Conversion of Mevalonate to Isopentenyl Diphosphate and Dimethylallyl Diphosphate. In stage 2 of the cholesterol biosynthetic pathway, phosphorylation and decarboxylation of mevalonate leads to the generation of isopentenyl diphosphate, which is isomerized to dimethylallyl diphosphate. Stage 3: Formation of Squalene from Four Isopentenyl Diphosphates and Two Dimethylallyl Diphosphates Reactions in stage 3 of the cholesterol biosynthetic pathway can be divided into two steps. In the stage 3a reactions, geranyl diphosphate is formed by a head-to-tail linkage of dimethylallyl diphosphate and isopentenyl diphosphate. Addition of another isopentenyl diphosphate to the head of geranyl diphosphate leads to the formation of farnesyl diphosphate. In the stage 3b reaction, two farnesyl diphosphate molecules are linked head-to-head to release two molecules of pyrophosphate and form the C30 compound squalene Stage 4: Cyclization of Squalene and Lanosterol Modification to Form Cholesterol Reactions in stage 4 of the cholesterol biosynthetic pathway. In animals, cyclase enzymes catalyze bond rearrangements that convert squalene 2,3-epoxide into the four-ringed sterol molecule lanosterol. The conversion of lanosterol to cholesterol requires 19 additional steps and the removal of three methyl groups.
Bile acid binding resins are used to lower serum cholesterol levels by increasing the rate of bile acid excretion, which shunts cholesterol away from lipoprotein particle export
The bile acid binding resin cholestyramine is an insoluble mixed ionic polymer that binds to bile acids with high affinity. The bond coming from the center of the ring indicates that the substituent can be attached to variable positions in the ring. b. Drinking an oral suspension of insoluble resins results in the excretion of bile acid-resin complexes, triggering the production of more bile acids from cholesterol esters and thus lowering the total cholesterol pool.
Three processes control cholesterol homeostasis in liver cells
The first is endocytosis of LDL particles by LDL receptors, which involves recycling of LDL receptors and recovery of the cholesterol cargo (black numbered circles). The second is de novo cholesterol biosynthesis by liver enzymes (blue numbered circles). This process is subject to inhibition by statin drugs that target the enzyme HMG-CoA reductase. The third is stimulation of LDL receptor gene expression by low intracellular cholesterol levels through activation of the transcription factor SREBP (green numbered circles). This process leads to increased levels of LDL receptors on the cell surface and higher rates of LDL endocytosis
Cardiovascular disease is responsible for up to half of all deaths in some countries, including the United States.
The main problem is arterial blockage, a condition called atherosclerosis, which leads to fatal heart attacks and strokes.
These four reactions together convert palmitoyl-CoA (C16) into myristoyl-CoA (C14) and in the process generate 1 FADH2, 1 NADH, and 1 acetyl-CoA.
The myristoyl-CoA product becomes the substrate for another round of β oxidation, resulting in the production of one more molecule each of FADH2, NADH, and acetyl-CoA. The complete oxidation of palmitoyl-CoA requires seven cycles of the four-step β-oxidation cycle to yield 8 acetyl-CoA + 7 FADH2 + 7 NADH.
The ER elongation reactions are most active in animal cells and use the same types of reactions used by fatty acid synthase to add C2 units to a fatty acyl substrate.
The primary difference between the ER elongation enzymes and fatty acid synthase is that the coenzyme A moiety of malonyl-CoA functions as the carrier molecule rather than ACP
Ceramide
The simplest sphingolipid, with a single hydrogen as its head group. is a fatty acylated form of sphinganine and is derived from palmitoyl-CoA and the amino acid serine.
The β-oxidation pathway consists of four reactions, which are repeated for the degradation of each two-carbon segment of the hydrocarbon chain
The β-oxidation pathway consists of four reaction steps, one of which is inhibited by the compound hypoglycin A found in unripe ackee fruit. a. (1) Oxidation of the fatty acyl-CoA substrate using an enzyme-linked FAD moiety forms a trans C= C bond between the α and β carbons. (long-chain (C12 to C18), medium-chain (C4 to C14), and short-chain (C4 to C8) acyl-CoA dehydrogenases) (2) Hydration across the C= C bond adds a hydroxyl group to the β carbon. (3) A second oxidation reaction, this time using NAD+, removes two electrons and generates a C= O at the β carbon. (4) Thiolase-mediated cleavage at the β carbon releases acetyl-CoA and an acyl-CoA product that is two carbons shorter than the substrate.
The desaturating enzymes in animal cells are membrane-bound ER proteins that use molecular oxygen (O2) as the oxidant.
These desaturating enzymes are called mixed-function oxidases because they use O2 in the reaction mechanism
the citrate shuttle provides a mechanism to stimulate fatty acid synthesis in the cytosol when acetyl-CoA accumulates in the mitochondrial matrix.
This buildup of mitochondrial acetyl-CoA occurs when glucose levels are high and the citrate cycle is feedback-inhibited by a high energy charge in the cell.
When AMP levels increase as a function of decreased glucose and low energy charge, AMP binds to both AMPK and AMPK kinase
This leads to the phosphorylation and depolymerization of acetyl-CoA carboxylase, which decreases rates of fatty acid synthesis, thereby providing acetyl-CoA for energy conversion reactions in the citrate cycle.
Ketogenesis Is a Salvage Pathway for Acetyl-CoA
When carbohydrate sources are limited because of starvation or when glucose homeostasis is defective in the case of diabetes, ongoing β oxidation in liver cell mitochondria results in the buildup of excess acetyl-CoA
Although acetyl-CoA is used directly as the anchoring primer in the first cycle of fatty acid synthesis
all subsequent cycles derive the two carbons that lengthen the chain from malonyl-CoA
Triacylglycerols are generated by
attaching a third fatty acid to phosphatidic acid at C-3. For simplicity, the hydrocarbon tail of the fatty acid is denoted by "FA." Glycerol-3-P can be generated from reduction of dihydroxyacetone phosphate or phosphorylation of glycerol
the O2 is not incorporated into the fatty acid product
but rather serves only as a strong oxidant to strip 2 e− from the fatty acid substrate.
16.1 Fatty Acid Oxidation and Ketogenesis
by the citrate cycle reactions are essential processes for maintenance of metabolic homeostasis in terrestrial animals, which use lipids as their primary energy reserve
Even the brain, which prefers glucose as an energy source
can adapt to using ketone bodies as chemical energy during times of extreme starvation
In the second step of the reaction
the fatty acyl- adenylate intermediate is attacked by the thiol group of CoA, forming the thioester fatty acyl-CoA product and releasing AMP.
Peroxisomal fatty acid oxidation
degrades very- long-chain fatty acids using specific enzymes that catalyze the same reactions present in mitochondria. The FAD/FADH2 redox pair in acyl-CoA dehydrogenase donates its electron pair to O2, generating H2O2, which is neutralized by peroxisomal catalase. The colorized electron micrograph of a peroxisome shows a dense region corresponding to the crystalline, protein-rich core.
Both triacylglycerols and glycerophospholipids are derived from
diacylglycerol-3-phosphate, also called phosphatidic acid
The three sources of cholesterol in lipoproteins are
dietary cholesterol; cholesterol biosynthesized in the liver; and cholesterol stored in peripheral tissues
Ketoacidosis
excessive production of ketones, making the blood acid. is a condition caused by low blood pH, which can occur when ketogenesis produces more aceto- acetate and d-β-hydroxybutyrate than can be used by the peripheral tissues.
The eukaryotic fatty acid degradation and synthesis pathways are complementary with respect to substrates and products; however, there are important differences in these two pathways to avoid futile cycling.
fatty acid degradation occurs in the mitochondrial matrix and uses FAD and NAD+ as oxidants. Eukaryotic fatty acid degradation requires multiple enzymes for each reaction cycle and uses coenzyme A as the acetyl group anchor. Lastly, the rate-limiting step in fatty acid degradation is carnitine-mediated transport into the mitochondrial matrix fatty acid synthesis occurs in the cytosol and depends on NADPH serving as a reductant. once malonyl-CoA is formed from acetyl-CoA and CO2 by the enzyme acetyl-CoA carboxylase, the reaction cycle in fatty acid synthesis is catalyzed by a single multifunctional enzyme called fatty acid synthase and uses acyl carrier protein (ACP) as the hydrocarbon anchor. The rate-limiting step in fatty acid synthesis is generation of the reaction cycle substrate malonyl-CoA.
Atherosclerotic plaques
form when injury occurs to the endothelial cell lining, allowing LDL particles to invade and initiate an immune response. The plaques contain cholesterol and fat deposits, macrophage foam cells, and fibrous material.
The biotin-dependent enzyme acetyl-CoA carboxylase, carries out three activities:
functioning as a biotin carboxylase, a biotin carrier, and a carboxyltransferase
high-density lipoproteins (HDLs)
have a high percentage of protein compared to lipid and have the highest density.
Vytorin
is a combination drug containing both simvastatin and ezetimibe and was developed to decrease serum LDL levels and lower the risk of cardiovascular disease.
The regulatory enzyme AMP-activated protein kinase (AMPK) Figure 16.34!!!!!!!!!!
is activated by low energy charge in the cell (high levels of AMP) and is an important metabolic sensor that controls the activity of many key enzymes in both anabolic and catabolic pathways.
atherosclerosis
is characterized by the buildup of fibrous tissue in arterial walls. This fibrous tissue contains, among other things, large deposits of cholesterol-rich lipids.
Excess glucose from eating too many non-fat high-carbohydrate foods
is converted to triacylglycerol in hepatocytes and exported to adipose tissue as VLDL particles. Under conditions of excess carbohydrates in the liver, flux through the citrate cycle is inhibited by high energy charge in the cell (high ATP, low ADP), thereby stimulating citrate export from the mitochondrial matrix.
increasing bile acid excretion by ingesting insoluble resins that bind bile acids with high affinity
is one of the available treatments to reduce overall cholesterol levels in the body
explanation for why LDL is bad and HDL is good
is related to differences in both cholesterol content and the function of lipoproteins contained in LDL and HDL particles
Although ketogenesis is an important survival mechanism
it can also lead to pathologic conditions if acetoacetate and d-β-hydroxybutyrate levels in the blood become too high
In order for the succinyl-CoA produced by odd-chain fatty acid oxidation of tricosanoyl-CoA to be used by energy conversion reactions
it must first be converted to malate, which is then decarboxylated in the cytosol by malic enzyme to yield pyruvate. Transport of pyruvate into the mitochondrial matrix under conditions of low energy charge leads to a net yield of one acetyl-CoA for each succinyl-CoA that enters the citrate cycle from odd-chain fatty acid oxidation. The total yield of acetyl-CoA from tricosanoyl-CoA oxidation is therefore 10 + 1 = 11 acetyl-CoA
But elevated levels of cholesterol-transporting lipoproteins in the blood, called low-density lipoproteins (LDLs)
leads to the formation of plaques in the lining of blood vessels.
Because flux through the glycolytic pathway is increased when glucose levels are elevated
much of this cytosolic NADH is generated by the glyceraldehyde-3-phosphate dehydrogenase step
The Arabian camel, desert kangaroo rat, and hibernating grizzly bear survive long periods of time without drinking H2O by
oxidizing stored triacylglycerols, which generates ∼ 130 mol of H2O per mole of
The primary product of the fatty acid synthase reactions in most cells is?
palmitate, which is then used as a substrate for both elongation and desaturation reactions to produce a variety of saturated and unsaturated fatty acids.
Citrate binding to phosphorylated acetyl-CoA carboxylase
partially activates the enzyme by stimulating polymerization in the absence of insulin signaling.
glucagon stimulates
phosphorylation and depolymerization of acetyl-CoA carboxylase through activation of AMP-activated protein kinase
Acetyl-CoA carboxylase activity is stimulated by
protein polymerization
Fatty acid synthesis is accomplished by
repeated reaction cycles within fatty acid synthase, each cycle adding two carbons at a time to the growing fatty acid chain.
Formation of fatty acyl-CoA by fatty acyl-CoA synthetase
requires a two-step reaction involving formation of an enzyme-bound adenylate intermediate and subsequent hydrolysis of pyrophosphate. The combined reactions catalyzed by fatty acyl-CoA synthetase and pyrophosphatase are highly exergonic (∆G°′ = -34 kJ/mol). Pi = inorganic phosphate. 2 ATP are required to phosphorylate the AMP product and regenerate ATP using the enzymes adenylate kinase and nucleoside diphosphate kinase.
Ketogenesis
salvages acetyl-CoA from liver mitochondria and converts it to acetoacetate and D-β- hydroxybutyrate (ketone bodies), which are exported from the liver to skeletal and cardiac muscle where they are used for energy conversion. Flux through the ketogenic pathway is increased when glucose levels are low inside liver cells due to starvation or diabetes. Acetyl-CoA builds up under these conditions because oxaloacetate is used to make phosphoenolpyruvate for the gluconeogenic pathway, thereby decreasing flux through the citrate cycle. The ketone bodies acetoacetate and D-β-hydroxybutyrate are formed from two molecules of acetyl-CoA in a three-step reaction pathway.
The two major classes of sphingolipids are
sphingophospholipids, such as sphingomyelin, and sphingoglycolipids, which include glucocerebroside and lactosylceramide. They are all derived from ceramide.
