Humboldt State University ® Department of Chemistry

Richard A. Paselk

Chem 438

Introductory Biochemistry

Spring 2010

Lecture Notes: 26 April

© R. Paselk 2006
 
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beta-oxidation of Fatty Acids, cont.

Once inside the mitochodrial matrix fatty acyl CoA can be broken down in the matrix by the fatty acid Beta-oxidation cycle [slide] as shown in Figure 16.19, and the Beta-oxidation scheme in your Biochemistry Packets. Note that the first three reactions of Beta-oxidation are the "mainline sequence" reactions we've already seen in the TCA Cycle. So you already know nearly all the reactions! The last reaction of the cycle releases an acetyl-CoA via a Claisen cleavage reaction (like an aldol cleavage but for esters instead of aldehydes). Note the similarity to the Claisen condensation from organic chemistry:

Claisen condensation mechjanism diagram

but of course run in reverse, and with CoAS- substituting for the alkoxide ion in the cleavage reaction.

Energy Yield: If we calculate the energy production for the complete oxidation of palmitate (16 C 's) we get:

 Reaction Energy Product Factor Multiplier ATP Equiv.

 O's
FACoA Syn. AMP -2 1 -2
Flavin DH FADH2 1.5 (2) 7 10.5 (14)
NAD+ DH NADH 2.5 (3) 7 17.5 (21)  7

8 AcCoA's to Kreb's TCA Cycle
NADH 2.5 (3) x 3 8 60 (72)  24
GTP 1 8 8  0
FADH2 1.5 (2) 8 12 (16)  8
Total       106 (129)  46

If we look at ATP/C we get 106/16= 6.63, while for glucose we get 32/6= 5.33, and for hexanoate: 36/6= 6. Thus, as expected, the fatty acids, being more reduced on average, give more energy per carbon and per gram. Along with the fact that they are stored without water of hydration, unlike carbohydrates, we can see their advantage as energy storage molecules for mobile organisms.

Another measure of fuel use is the P/O ratio, the number of ATP's generated for each oxygen atom consumed. For palmitate P/O = 106/46 = 2.3. As a comparison the P/O for glucose = 32/12 = 2.67. Notice by this measure glucose is the better fuel in situation where oxygen is limiting, since glucose will give more ATP's per mL of oxygen.

beta-OXIDATION OF UNSATURATED FATTY ACIDS

One might think that since an unsaturated fatty acid is created during beta-oxidation that unsaturated fatty acids should be handled easily by this system. However two problems occur due to the high level of specificity of the enzymes involved:

Two new enzymes are required to handle these situations: Enoyl-CoA isomerase (isomerizes a cis-3,4-double bond to a trans-2,3-double bond), and 2,4-Dienoyl-CoA reductase (reduces the cis-4,5-double bond in the trans-2,3-cis-4,5-dienoyl-CoA derivative formed during beta-oxidation). The resulting products are then broken down by the beta-oxidation enzymes.

ODD-CHAIN FATTY ACIDS

Most biological fatty acids are of even-numbered carbon chains. However, some organisms, particularly in the arctic marine environment, have a relatively high odd-chain component. Thus in organisms such as traditional Eskimo (Innuit) and polar bears eating lots of seal blubber and fish, odd-chain fatty acids can constitute a significant dietary component. These fatty acids are handled normally through beta-oxidation until the last turn, where pentyl-CoA is cleaved into acetyl-CoA and propionyl-CoA. The propionyl-CoA is converted through a number of steps to succinyl-CoA. These steps involve addition of carbon dioxide (with ATP energy) and an isomerization requiring cobalamin derived from vitamin B12. The succinyl-CoA can then be metabolized normally via the TCA cycle to malate, then to PEP and then to either 2-PGA for gluconeogenesis or to Pyruvate for energy production. (Propionate metabolism is also important to ruminants, since it is produced as a fermentation product by their symbiotic bacteria from plant matter.)

KETONE BODIES

Introductory discusion of fat metabolism, exercise, and fasting.

Fatty acids can be used as the major fuel for tissues such as muscle, but they cannot cross the blood-brain barrier, and thus cannot be used by the central nervous system (CNS). This becomes a major problem during starvation (fasting), particularly for organisms such as ourselves in which CNS metabolism constitute a major portion of the resting basal metabolic rate. These organism must provide glucose to the CNS to provide for metabolic needs, and thus during the initial fasting period must break down substantial amounts of muscle tissue (protein) to provide the amino acid precursors of gluconeogenesis. Obviously the organism could not survive long under such a regime. What is needed is an alternate fuel source based on fat rather than muscle. The so-called ketone bodies serve this function:

ketone body structures

Note that only two of the ketone bodies are in fact ketones, and that acetone is an "unintentional" breakdown product resulting from the instability of acetoacetate at body temperature. Acetone is not available as fuel to any significant extent, and is thus a waste product.

CNS tissues can use ketone bodies any time, the problem is the normally very low concentrations (< 0.3 mM) compared to glucose (about 4 mM). Since the KM's for both are similar, the CNS doesn't begin to use ketone bodies in preference to glucose until their concentration exceed's the concentration of glucose in the serum.

The system becomes saturated at about 7 mM. The limiting factor in using ketone bodies then becomes the ability of the liver to synthesis them, which requires the induction of the enzymes required for acetoacetate biosynthesis. Normal glucose concentrations inhibit ketone body synthesis, thus the ketone bodies will only begin to be synthesized in high concentrations as serum glucose concentrations fall. As an example, ketone bodies might start at about 0.1 mM after an overnight fast, rise to 3 mM after a 3 day fast, and go to 7-8 mM with prolonged fasting (>24 days).

Ketogenesis

Ketogenesis occurs in the matrix of liver mitochondria. Fatty acids are first broken down to acetyl CoA via beta-oxidation (providing energy for liver metabolism from the reducing equivalents generated). The acetyl CoA is then used in ketogenesis:

Biosynthesis reactions for ketone body synthesis in teh liver

Depending on the status of the liver, acetoacetate can now be reduced to give D-beta-hydroxybutyrate, which delivers more reducing equivalents, and thus ATP equivalents, to the peripheral tissues at the expense of the liver:

reduction of acetoacetate to give D-beta-hydroxybutyrate

Pathway Diagrams

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Last modified 28 April 2010