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Chapter 23. Fatty Acid Catabolism Biochemistry by Reginald Garrett and Charles Grisham. Outline. How Are Fats Mobilized from Dietary Intake and Adipose Tissue? How Are Fatty Acids Broken Down? How Are Odd-Carbon Fatty Acids Oxidized? How Are Unsaturated Fatty Acids Oxidized?

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chapter 23

Chapter 23

Fatty Acid Catabolism

Biochemistry

by

Reginald Garrett and Charles Grisham

outline
Outline
  • How Are Fats Mobilized from Dietary Intake and Adipose Tissue?
  • How Are Fatty Acids Broken Down?
  • How Are Odd-Carbon Fatty Acids Oxidized?
  • How Are Unsaturated Fatty Acids Oxidized?
  • Are There Other Ways to Oxidize Fatty Acids?
  • What Are Ketone Bodies, and What Role Do They Play in Metabolism?
23 1 how are fats mobilized from dietary intake and adipose tissue
23.1 – How Are Fats Mobilized from Dietary Intake and Adipose Tissue?
  • Triacylglycerols represent the major energy input in the modern American diet
    • Provides 30-60 % of calories
slide4
Triacylglycerols represent the major energy input in the modern American diet
    • Provides 30-60 % of calories
  • Triacylglycerols are also the major form of stored energy in the body (80%)
why fatty acids
Why Fatty Acids?

(For energy storage?)

  • Two reasons:
    • The carbon in fatty acids (mostly -CH2- groups) is reduced (so its oxidation yields the most energy possible).
    • Fatty acids are not hydrated (as mono- and polysaccharides are), so they can pack more closely in storage tissues
slide6
Triacylglycerols represent the major energy input in the modern American diet
    • Provides 30-60 % of calories
  • Triacylglycerols are also the major form of stored energy in the body
  • Hormones (glucagon, epinephrine, ACTH) trigger the release of fatty acids from adipose tissue (Figure 23.2 & chapter 32)
slide7

Triacylglycerol lipase

Hormone-sensitive lipase

Figure 23.2 Liberation of fatty acids from triacylglycerols in adipose tissue is hormone-dependent.

slide8
Triacylglycerols represent the major energy input in the modern American diet
    • Provides 30-60 % of calories
  • Triacylglycerols are also the major form of stored energy in the body
  • Hormones (glucagon, epinephrine, ACTH) trigger the release of fatty acids from adipose tissue (Figure 23.2 & chapter 32)
  • Degradation of dietary fatty acids occurs primarily in the duodenum (Figure 23.3 & chapter 24)
slide9

Figure 23.3(a) The pancreatic duct secretes digestive fluids into the duodenum, the first portion of the small intestine. (b) Hydrolysis of triacylglycerols by pancreatic and intestinal lipases. Pancreatic lipases cleave fatty acids at the C-1 and C-3 positions. Resulting monoacylglycerols with fatty acids at C-2 are hydrolyzed by intestinal lipases. Fatty acids and monoacylglycerols are absorbed through the intestinal wall and assembled into lipoprotein aggregates termed chylomicrons (discussed in Chapter 24).

slide10

Figure 23.4 In the small intestine, fatty acids combine with bile salts in mixed micelles, which deliver fatty acids to epithelial cells that cover the intestinal villi. Triacylglycerols are formed within the epithelial cells.

23 2 how are fatty acids broken down
23.2 – How Are Fatty Acids Broken Down?
  • Franz Knoop showed that fatty acids must be degraded by removal of 2-C units (acetate)
  • Albert Lehninger showed that this occurred in the mitochondria
  • F. Lynen and E. Reichart showed that the 2-C unit released is acetyl-CoA, not free acetate
  • The process begins with oxidation of the carbon that is "b" to the carboxyl carbon, so the process is called"b-oxidation"
slide12

Figure 23.5 Fatty acids are degraded by repeated cycles of oxidation at the β-carbon and cleavage of the Cα-Cβ bond to yield acetate units, in the form of acetyl-CoA.

coenzyme a activates fatty acids for degradation
Coenzyme A activates Fatty Acids for degradation
  • The process ofb-oxidation begins with the formation of a thiol ester bond between the FA and the thiol group of CoA
  • Acyl-CoA synthetase condenses fatty acids with CoA, with simultaneous hydrolysis of ATP to AMP and PPi (acyl-CoA ligase or fatty acid thiokinase)
slide14

This reaction normally occurs at the outer mitochondrial membrane or at the surface of the endoplasmic reticulum

Figure 23.7 The mechanism of the acyl-CoA synthetase reaction involves fatty acid carboxylate attack on ATP to form an acyl-adenylate intermediate. The fatty acyl CoA thioester product is formed by CoA attack on this intermediate.

carnitine as a carrier
Carnitine as a Carrier

Carnitine carries fatty acyl groups across the inner mitochondrial membrane

  • Short chain fatty acids are transporteddirectly into the mitochondrial matrix
  • Long-chain fatty acids cannot be directly transported into the matrix
    • Long-chain FAs are converted to acyl-carnitines and are then transported in the cell
  • Acyl-CoA are formed inside the inner membrane
slide16

Figure 23.8 The formation of acylcarnitines and their transport across the inner mitochondrial membrane. The process involves the coordinated actions of carnitine acyltransferases on both sides of the membrane and of a translocase that shuttles O-acylcarnitines across the membrane.

oxidation of fatty acids
-Oxidation of Fatty Acids

A Repeated Sequence of 4 Reactions

  • First 3 reactions is to create a carbonyl group on the -C
  • Fourth cleaves the "-keto ester" in a reverse Claisen condensation
  • Products: an acetyl-CoA and a fatty acid (two carbons shorter)
  • The first three reactions are crucial and classic - we will see them in other pathways (TCA cycle)
slide18

Figure 23.9The b-oxidation of saturated fatty acids involves a cycle of four enzyme-catalyzed reactions.

1 acyl coa dehydrogenase
1. Acyl-CoA Dehydrogenase

Oxidation of the C-C bond

  • A family of membrane-bound (VLCAD) and three soluble matrix enzymes (LCAD, MCAD, and SCAD)
  • Mechanism involves proton abstraction, followed by double bond formation and hydride removal by FAD
  • Electrons are passed to an electron transfer flavoprotein, and then to the electron transport chain (chapter20)
slide21

14C and longer

Figure 23.10 Very long-chain fatty acids proceed through several cycles of β-oxidation (left) via membrane-bound enzymes in mitochondria, before becoming substrates for the separate soluble enzymes of β-oxidation (right).

slide22

ETF: electron transfer flavoprotein

Figure 23.12 The acyl-CoA dehydrogenase reaction. The two electrons removed in this oxidation reaction are delivered to the electron transport chain in the form of reduced coenzyme Q (UQH2).

2 enoyl coa hydratase
2. Enoyl-CoA Hydratase

Adds water across the double bond

  • The reaction is catalyzed by enoyl-CoA hydratase
    • Also called crotonases
  • Normal reaction converts trans-enoyl-CoA to L--hydroxyacyl-CoA
3 l hydroxyacyl coa dehydrogenase
3. L-Hydroxyacyl-CoA Dehydrogenase

Oxidizes the -Hydroxyl Group

  • This enzyme is completely specific for L-hydroxyacyl-CoA
  • NADH produced in this reaction represents metabolic energy
4 thiolase ketothiolase
4. Thiolase (-ketothiolase)

Cleavage of the b-ketoacyl-CoA

  • Cysteine thiolate on enzyme attacks the -carbonyl group of acyl-CoA
  • Thiol group of a new CoA attacks the shortened chain, forming a new, shorter acyl-CoA
  • Formation of a new thioester, this reaction is favorable and drives other three previous reactions of the b-oxidation
summary of oxidation
Summary of -Oxidation

Repetition of the cycle yields a succession of acetate units

  • Thus, palmitic acid yields eight acetyl-CoAs
  • Complete -oxidation of one palmitic acid yields 106 molecules of ATP
  • Large energy yield is consequence of the highly reduced state of the carbon in fatty acids
  • This makes fatty acids the fuel of choice for migratory birds and many other animals (70%)
slide30
Migratory Birds Travel Long Distances on Energy From Fatty Acid Oxidation
  • Because they represent the most highly concentrated form of stored biological energy, fatty acids are the metabolic fuel of choice for sustaining the long flights of migratory birds
  • These prodigious feats are accomplished by storing large amounts of triacylglycerols prior to flight
  • These birds are often 70% fat by weight when migration begins(compared with values of 30% and less for nonmigratory birds)
slide31

The ruby-throated hummingbird flies nonstop across the Gulf of Mexico

American golden plovers fly from Alaska to Hawaii nonstop – 3300 km in 35 hours – more than 250,000 wing beats

slide32
Fatty Acid Oxidation is an Important Source of Metabolic Water for Some Animals
  • Large amounts of metabolic water are generated by b-oxidation
  • For certain animals, the oxidation of stored fatty acids can be a significant source of dietary water
    • Desert animals (such as gerbils)
    • Killer whales (which do not drink seawater)
    • Camels (whose hump is a large fat deposit)
  • Metabolism of fatty acids from such stores provides needed water, as well as metabolic energy, during periods when drinking water is not available
23 3 how are odd carbon fatty acids oxidized
23.3 – How Are Odd-Carbon Fatty Acids Oxidized?

Oxidation yields propionyl-CoA

  • Odd-carbon fatty acids are metabolized normally, until the last three-C fragment (propionyl-CoA) is reached
  • Three reactions convert propionyl-CoA to succinyl-CoA (Figure 23.18)
    • Propionyl-CoA carboxylase (biotin)
    • Methylmalonyl-CoA epimerase
    • Methylmalonyl-CoA mutase (B12)
  • Succinyl-CoA can enter the TCA cycle
slide35

Figure 23.19 The methylmalonyl-CoA epimerase mechanism involves a resonance-stabilized carbanion at the a-position.

Figure 23.18 The conversion of propionyl-CoA (formed from b-oxidation of odd-carbon fatty acids) to succinyl-CoA is carried out by a trio of enzymes as shown. Succinyl-CoA can enter the TCA cycle.

slide36

Conversion of inactive vitamin B12 to active 5'-deoxyadenosylcobalamin involves three steps

    • Two flavoprotein reductases convert Co3+ to Co2+ and then to Co+
    • Co+ is a powerful nucleophile, which can attack the C-5’ of ATP to form 5-deoxyadenosylcobalamin
23 4 how are unsaturated fatty acids oxidized
23.4 – How Are Unsaturated Fatty Acids Oxidized?

Monounsaturated fatty acids:

  • Oleic acid, palmitoleic acid
  • Normal -oxidation for three cycles
  • cis-3-acyl-CoA cannot be utilized by acyl-CoA dehydrogenase
  • Enoyl-CoA isomerase converts this to trans- 2-acyl-CoA

b-oxidation continues from this point

slide39

Figure 23.21 b-Oxidation of unsaturated fatty acids. In the case of oleoyl-CoA, three b-oxidation cycles produce three molecules of acetyl-CoA and leave cis-D3-dodecenoyl-CoA. Rearrangement of enoyl-CoA isomerase gives the trans-D2 species, which then proceeds normally through the b-oxidation pathway.

polyunsaturated fatty acids
Polyunsaturated Fatty Acids

Slightly more complicated

  • Same as for oleic acid, but only up to a point:
    • 3 cycles of -oxidation
    • enoyl-CoA isomerase
    • 1 more round of -oxidation
    • trans-2, cis-4 structure is a problem
  • 2,4-Dienoyl-CoA reductase to the rescue
23 5 are there other ways to oxidize fatty acids
23.5 – Are There Other Ways to Oxidize Fatty Acids?
  • Peroxisomal & Glyoxysomal-oxidation
  • Branched-chain -oxidation
  • -oxidation (dicarboxylic acids)
peroxisomal oxidation requires fad dependent acyl coa oxidase
Peroxisomal -Oxidation requires FAD-dependent acyl-CoA oxidase
  • Peroxisomes - organelles that carry out flavin-dependent oxidations, regenerating oxidized flavins by reaction with O2 to produce H2O2
    • Similar to mitochondrial -oxidation, but initial double bond formation is by acyl-CoA oxidase
    • Electrons go to O2 rather than e- transport
    • Fewer ATPs result
  • Similar b-oxidation enzymes are also found in glyoxysomesin plant
slide44

Figure 23.23 The acyl-CoA oxidase reaction in peroxisomes. Electrons captured as FADH2 are used to produce the hydrogen peroxide required for degradative processes in peroxisomes and thus are not available for eventual generation of ATP.

branched chain fatty acids
Branched-Chain Fatty Acids

An alternative to -oxidation is required

  • Branched chain FAs with branches at odd-number carbons are not good substrates for -oxidation
  • -oxidation is an alternative
  • Phytanic acid -oxidase decarboxylates with oxidation at the alpha position
  • -oxidation occurs past the branch
slide46

Figure 23.24Branched-chain fatty acids are oxidized by a-oxidation, as shown for phytanic acid. The product of the phytanic acid oxidase, pristanic acid, is a suitable substrate for normal b-oxidation. Isobutyryl-CoA and propionyl-CoA can both be converted to succinyl-CoA, which can enter the TCA cycle.

slide47

-oxidation (dicarboxylic acids)

  • In ER
  • Cytochrome P-450
  • O2

Figure 23.25 Dicarboxylic acids can be formed by oxidation of the methyl group of fatty acids in a cytochrome P-450-dependent reaction.

23 6 what are ketone bodies and what role do they play in metabolism
23.6 – What Are Ketone Bodies, and What Role Do They Play in Metabolism?

A special source of fuel and energy for certain tissues

  • Some of the acetyl-CoA produced by fatty acid oxidation in liver mitochondria is converted to acetone, acetoacetate and -hydroxybutyrate
    • These are called "ketone bodies"
    • Source of fuel for brain, heart and muscle
    • Major energy source for brain during starvation
    • They are transportable forms of fatty acids
slide49

Ketone Body synthesis

  • In liver mitochondrial matrix
  • First reaction is reverse thiolase
  • Second reaction makes HMG-CoA
  • Third reaction converts HMG-CoA to acetoacetate and acetyl-CoA by HMG-CoA lyase
  • Acetoacetate is reduced to b-hydroxybutyrate by b-hydroxybutyrate dehydrogenase
slide50

Acetoacetate and b-hydroxybutyrate are transported through the blood from liver to target organ

  • Acetoacetate and b-hydroxybutyrate are converted to acetyl-CoA

Figure 23.27 Reconversion of ketone bodies to acetyl-CoA in the mitochondria of many tissues (other than liver) provides significant metabolic energy.