Biochemistry. The chemical reactions of living cells,

1040 Pages·2003·22.75 MB·English

by  Metzler D.

Table of Contents
Volume 1
Chapter 1. The Scene of Action 1
Chapter 2. Amino Acids, Peptides, and Proteins 39
Chapter 3. Determining Structures and Analyzing Cells 95
Chapter 4. Sugars, Polysaccharides, and Glycoproteins 161
Chapter 5. The Nucleic Acids 199
Chapter 6. Thermodynamics and Biochemical Equilibria 281
Chapter 7. How Macromolecules Associate 325
Chapter 8. Lipids, Membranes, and Cell Coats 379
Chapter 9. Enzymes: The Catalysts of Cells 455
Chapter 10. An Introduction to Metabolism 505
Chapter 11. The Regulation of Enzymatic Activity and Metabolism 535
Chapter 12. Transferring Groups by Displacement Reactions 589
Chapter 13. Enzymatic Addition, Elimination, Condensation,
and Isomerization: Roles for Enolate and Carbocation
Intermediates 677
Chapter 14. Coenzymes: Nature’s Special Reagents 719
Chapter 15. Coenzymes of Oxidation – Reduction Reactions 765
Chapter 16. Transition Metals in Catalysis and Electron Transport 837
Table of Contents
Volume 2
Chapter 17. The Organization of Metabolism 938
Chapter 18. Electron Transport, Oxidative Phosphorylation,
and Hydroxylation 1012
Chapter 19. The Chemistry of Movement 1088
Chapter 20. Some Pathways of Carbohydrate Metabolism 1128
Chapter 21. Specific Aspects of Lipid Metabolism 1180
Chapter 22. Polyprenyl (Isoprenoid) Compounds 1226
Chapter 23. Light and Life 1272
Chapter 24. The Metabolism of Nitrogen and Amino Acids 1358
Chapter 25. Metabolism of Aromatic Compounds and Nucleic
Acid Bases 1420
Chapter 26. Biochemical Genetics 1472
Chapter 27. Organization, Replication, Transposition, and Repair
of DNA 1528
Chapter 28. The Transcription of Genes 1602
Chapter 29. Ribosomes and the Synthesis of Proteins 1668
Chapter 30. Chemical Communication Between Cells 1740
Chapter 31. Biochemical Defense Mechanisms 1830
Chapter 32. Growth and Development 1878
Front matter Vol 2 10 2/14/03, 3:03 PM
938 Chapter 17. The Organization of Metabolism
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Contents
939 A. The Oxidation of Fatty Acids 978 I. Reducing Agents for Biosynthesis
939 1. Beta Oxidation 980 1. Reversing an Oxidative Step with a Strong
941 Peroxisomal beta oxidation Reducing Agent
941 Unsaturated fatty acids 980 2. Regulation of the State of Reduction of the NAD
942 Branched-chain fatty acids and NADP Systems
942 Oxidation of saturated hydrocarbons 981 3. Reduced Ferredoxin in Reductive Biosynthesis
942 Alpha oxidation and omega oxidation 982 J. Constructing the Monomer Units
944 2. Carnitine and Mitochondrial Permeability 982 1. Carbonyl Groups in Chain Formation and Cleavage
944 3. Human Disorders of Fatty Acid Oxidation 982 2. Starting with CO2
945 4. Ketone Bodies 985 3. Biosynthesis from Other Single-Carbon
947 B. Catabolism of Propionyl Coenzyme A and Propionate Compounds
947 1. The Malonic Semialdehyde Pathways 987 4. The Glyoxylate Pathways
950 2. The Methylmalonyl-CoA Pathway of Propionate 989 5. Biosynthesis of Glucose from Three-Carbon
Utilization Compounds
950 C. The Citric Acid Cycle 990 6. Building Hydrocarbon Chains with Two-Carbon
950 1. A Clever Way to Cleave a Reluctant Bond Units
952 2. Synthesis of the Regenerating Substrate 990 7. The Oxoacid Chain Elongation Process
Oxaloacetate 992 8. Decarboxylation as a Driving Force in Biosynthesis
952 3. Common Features of Catalytic Cycles 992 9. Stabilization and Termination of Chain Growth by
953 4. Control of the Cycle Ring Formation
957 5. Catabolism of Intermediates of the Citric 992 10. Branched Carbon Chains
Acid Cycle 993 K. Biosynthesis and Modification of Polymers
958 D. Oxidative Pathways Related to the Citric Acid Cycle 993 1. Peptides and Proteins
958 1. The γ-Aminobutyrate Cycle 994 2. Polysaccharides
958 2. The Dicarboxylic Acid Cycle 995 3. Nucleic Acids
960 E. Catabolism of Sugars 995 4. Phospholipids and Phosphate –Sugar Alcohol
960 1. The Glycolysis Pathway Polymers
960 Formation of pyruvate 995 5. Irreversible Modification and Catabolism of
962 The further metabolism of pyruvate Polymers
962 2. Generation of ATP by Substrate Oxidation 996 L. Regulation of Biosynthesis
963 3. The Pentose Phosphate Pathways 997 1. Glycogen and Blood Glucose
964 An oxidative pentose phosphate cycle 997 Insulin
965 Nonoxidative pentose phosphate pathways 999 Glucagon
965 4. The Entner – Doudoroff Pathway 999 2. Phosphofructo-1-Kinase in the Regulation of
966 F. Fermentation: “Life without Oxygen” Glycolysis
966 1. Fermentations Based on the Embden–Meyerhof 1000 3. Gluconeogenesis
Pathway 1000 4. Substrate Cycles
966 Homolactic and alcoholic fermentations 1000 5. Nuclear Magnetic Resonance, Isotopomer
966 Energy relationships Analysis, and Modeling of Metabolism
967 Variations of the alcoholic and homolactic 1002 6. The Fasting State
fermentations 1003 7. Lipogenesis
968 2. The Mixed Acid Fermentation
970 3. The Propionic Acid Fermentation 1006 References
971 4. Butyric Acid and Butanol-Forming Fermentations 1010 Study Questions
972 5. Fermentations Based on the Phosphogluconate
and Pentose Phosphate Pathways Boxes
972 G. Biosynthesis 943 Box 17-A Refsum Disease
973 1. Metabolic Loops and Biosynthetic Families 949 Box 17-B Methylmalonic Aciduria
973 2. Key Intermediates and Biosynthetic Families 954 Box 17-C Use of Isotopic Tracers in Study of the
973 H. Harnessing the Energy of ATP for Biosynthesis Tricarboxylic Acid Cycle
974 1. Group Activation 957 Box 17-D Fluoroacetate and “Lethal Synthesis”
976 2. Hydrolysis of Pyrophosphate 985 Box 17-E 14C and the Calvin–Benson Cycle
977 3. Coupling by Phosphorylation and Subsequent 1002 Box 17-F Lactic Acidemia and Other Deficiencies
Cleavage by a Phosphatase in Carbohydrate Metabolism
977 4. Carboxylation and Decarboxylation: Synthesis of 1003 Box 17-G Diabetes Mellitus
Fatty Acids
Tables
968 Table 17-1 Products of the Mixed Acid Fermentation
by E. coli at Low and High Values of pH
975 Table 17-2 “Activated” Groups Used in Biosynthesis
998 Table 17-3 Some Effects of Insulin on Enzymes
Ch 17IND page - E - 938 2/14/03, 11:14 AM
939
The Organization of Metabolism
17
F
Galuttcyo asceids
POFyArDCuβHv CO2aOHtO3xe–iNdAaDtiHoCnO2 NACDAHH3cHetCyOlOS-3C– oC–AoOAOHHC C COOO– CHH2oCHCOAOiCt-–rSaOCHCtOHeOO– – H2O H2CHOOCC– COO– H2O
fβ
ca
o
c
toaionc tOt cnrdptuiyvx ycrr ie raed aruicacnasivcitd dotmiaiosn toc eni( ntyo a otsocbfac l fokgehfv elo(usern ci)pdgolhrsaietac–)OeOH;HC C –OOCOHOHCHOH– C2OHCOO––O2ONHOCFHA222OCGDH2THCHOPO2– H2COOOTCE–HrCal2SenhcNCsatprCAiOonooAD2nrtH H2COAOOCD–H2PCNAO +OCTA– OPDi2HH2COOOC– CHOCOHHO–2COC–OOC– HCOCOO– –
in cytosol of animal cells Citric Acid Cycle
Metabolism involves a bewildering array of chem- phosphate ions using the sequence shown in Eq. 10-1
ical reactions, many of them organized as complex (p. 508). There are isoenzymes that act on short-,
cycles which may appear difficult to understand. Yet, medium-, and long-chain fatty acids. Yeast contains
there is logic and orderliness. With few exceptions, at least five of these.1 In every case the acyl group is
metabolic pathways can be regarded as sequences of activated through formation of an intermediate acyl
the reactions considered in Chapters 12 – 16 (and sum- adenylate; hydrolysis of the released pyrophosphate
marized in the table inside the back cover) which are helps to carry the reaction to completion (see discus-
organized to accomplish specific chemical goals. In sion in Section H).
this chapter we will examine the chemical logic of the
major pathways of catabolism of foods and of cell
constituents as well as some reactions of biosynthesis 1. Beta Oxidation
(anabolism). A few of the sequences have already
been discussed briefly in Chapter 10. The reaction steps in the oxidation of long-chain
acyl-CoA molecules to acetyl-CoA were outlined in
Fig. 10-4. Because of the great importance of this β
A. The Oxidation of Fatty Acids oxidation sequence in metabolism the steps are shown
again in Fig. 17-1 (steps b–e). The chemical logic
Hydrocarbons yield more energy upon combus- becomes clear if we examine the structure of the acyl-
tion than do most other organic compounds, and it is, CoA molecule and consider the types of biochemical
therefore, not surprising that one important type of reactions available. If the direct use of O2 is to be
food reserve, the fats, is essentially hydrocarbon in avoided, the only reasonable mode of attack on an
nature. In terms of energy content the component acyl-CoA molecule is dehydrogenation. Removal of
fatty acids are the most important. Most aerobic cells the α hydrogen as a proton is made possible by the
can oxidize fatty acids completely to CO2 and water, activating effect of the carbonyl group of the thioester.
a process that takes place within many bacteria, in the The β hydrogen can be transferred from the inter-
matrix space of animal mitochondria, in the peroxi- mediate enolate, as a hydride ion, to the bound FAD
somes of most eukaryotic cells, and to a lesser extent present in the acyl-CoA dehydrogenases that cata-
in the endoplasmic reticulum. lyze this reaction2–5 (step b, Fig. 17-1; see also Eq.
The carboxyl group of a fatty acid provides a point 15-23). These enzymes contain FAD, and the reduced
for chemical attack. The first step is a priming reaction coenzyme FADH2 that is formed is reoxidized by an
in which the fatty acid is converted to a water-soluble electron transferring flavoprotein (Chapter 15),
acyl-CoA derivative in which the α hydrogens of the which also contains FAD. This protein carries the
fatty acyl radicals are “activated” (step a, Fig. 17-1). electrons abstracted in the oxidation process to the
This synthetic reaction is catalyzed by acyl-CoA inner membrane of the mitochondrion where they
synthetases (fatty acid:CoA ligases). It is driven by enter the mitochondrial electron transport system,5a
the hydrolysis of ATP to AMP and two inorganic as depicted in Fig. 10-5 and as discussed in detail in
Ch 17IND page - E - 939 2/14/03, 11:15 AM
940 Chapter 17. The Organization of Metabolism
Chapter 18. Free fatty acids
The product of step b is always
a trans-⌬2-enoyl-CoA. One of the a ATP
see Eq. 10-1, p. 508
few possible reactions of this unsat-
urated compound is nucleophilic O
H H
addition at the β position. The
– C C
reacting nucleophile is an HO ion
R C S CoA
from water. This reaction step (step
H H
c, Fig. 17-1) is completed by addi-
Acyl-CoA
+
tion of H at the α position. The
resulting ␤-hydroxyacyl-CoA FAD
(3-hydroxyacyl-CoA) is dehydro- b Acyl-CoA dehydrogenase
+ The β
genated to a ketone by NAD (step
FADH
5b Oxidation 2
d). This series of three reactions is
Sequence H O
the β oxidation sequence.
At the end of this sequence,
C C
the β-oxoacyl-CoA derivative is R C S CoA
cleaved (Fig. 17-1, step e) by a
H
thiolase (see also Eq. 13-35). One
Enoyl-CoA
of the products is acetyl-CoA, which
H O
can be catabolized to CO through 2
2
the citric acid cycle. The other c Enoyl-CoA hydratase
product of the thiolytic cleavage is
Shortened acyl-CoA
an acyl-CoA derivative that is two is recycled, a 2 C fragment
O
being cut off each time
carbon atoms shorter than the original H OH
acyl-CoA. This molecule is recycled C C
through the β oxidation process, R CH2 S CoA
a two-carbon acetyl unit being β-Hydroxyacyl-CoA
removed as acetyl-CoA during each NAD+
turn of the cycle (Fig. 17-1). The
d β-Hydroxyacyl-CoA dehydrogenase
process continues until the fatty
+
NADH + H
acid chain is completely degraded.
If the original fatty acid contained O O
an even number of carbon atoms in
C C
a straight chain, acetyl-CoA is the
R CH2 S CoA
only product. However, if the
– +
original fatty acid contained an CoA S H
odd number of carbon atoms, β-Oxoacyl-CoA
propionyl-CoA is formed at
e Thiolase
the end.
O O
For every step of the β oxidation
R' (CH2)2 C CH3 C
sequence there is a small family of
S CoA S CoA
enzymes with differing chain length
R' = R – 2CH2 Acetyl-CoA
6,7
preferences. For example, in
When chain degradation is complete,
liver mitochondria one acyl-CoA
a short terminal piece remains:
dehydrogenase acts most rapidly Acetyl-CoA if R' = CH
3
on n-butyryl and other short-chain Propionyl-CoA if R' = CH2CH3 Oxidation through
citric acid cycle
acyl-CoA; a second prefers a sub-
strate of medium chain length such
as n-octanoyl-CoA; a third prefers
Figure 17-1 The β oxidation cycle for fatty acids. Fatty acids are converted to
long-chain substrates such as pal-
acyl-CoA derivatives from which 2-carbon atoms are cut off as acetyl-CoA to
mitoyl-CoA; and a fourth, substrates give a shortened chain which is repeatedly sent back through the cycle until
with 2-methyl branches. A fifth only a 2- or 3-carbon acyl-CoA remains. The sequence of steps b, c, and d also
enzyme acts specifically on isovaleryl- occurs in many other places in metabolism.
CoA. Similar preferences exist for
the other enzymes of the β oxida-
tion pathway. In Escherichia coli
Ch 17IND page - E - 940 2/14/03, 11:15 AM
A. The Oxidation of Fatty Acids 941
+
most of these enzymes are present as a complex of multi- are freely permeable to NAD , NADH, and acyl-CoA
8
functional proteins while the mitochondrial enzymes molecules. However, genetic experiments with yeast
9,10
may be organized as a multiprotein complex. and other recent evidence indicate that they are imper-
meable in vivo and that carrier and shuttle mechanisms
14,25
Peroxisomal beta oxidation. In animal cells β similar to those in mitochondria may be required.
5
oxidation is primarily a mitochondrial process, but
it also takes place to a limited extent within peroxi- Unsaturated fatty acids. Mitochondrial β oxi-
11–14 9
somes and within the endoplasmic reticulum. dation of such unsaturated acids as the ∆ -oleic acid
This “division of labor” is still not understood well. begins with removal of two molecules of acetyl-CoA
5
Straight-chain fatty acids up to 18 carbons in length to form a ∆ -acyl-CoA. However, further metabolism
appear to be metabolized primarily in mitochondria, is slow. Two pathways have been identified (Eq.
26–29b
but in the liver fatty acids with very long chains are 17-1). The first step for both is a normal dehydro-
13
processed largely in peroxisomes. There, a very genation to a 2-trans-5-cis-dienoyl-CoA. In pathway I
long-chain acyl-CoA synthetase acts on fatty acids this intermediate reacts slowly by the normal β oxida-
15
that contain 22 or more carbon atoms. In yeast all β tion sequence to form a 3-cis-enoyl-CoA intermediate
15,16
oxidation takes place in peroxisomes, and in most which must then be acted upon by an auxiliary enzyme,
17–18a 3 2
organisms, including green plants, the peroxi- a cis-∆ -trans-∆ -enoyl-CoA isomerase (Eq. 17-1, step c),
somes are the most active sites of fatty acid oxidation. before β oxidation can continue.
However, animal peroxisomes cannot oxidize short- The alternative reductase pathway (II in Eq. 17-1)
chain acyl-CoA molecules; they must be returned to is often faster. It makes use of an additional isomerase
16
the mitochondria. The activity of peroxisomes in which converts 3-trans, 5-cis-dienoyl-CoA into the
β oxidation is greatly increased by the presence of a 2-trans, 4-trans isomer in which the double bonds are
29
variety of compounds known as peroxisome prolif- conjugated with the carbonyl group. This permits
erators. Among them are drugs such as aspirin and removal of one double bond by reduction with NADPH
29a,29b
clofibrate and environmental xenobiotics such as as shown (Eq. 17-1, step f ). The peroxisomal
the plasticizer bis-(2-ethyl-hexyl)-
phthalate. They may induce as much O
as a tenfold increase in peroxisomal
5
11,12,19,19a R
β oxidation.
Several other features also distin-
a Acyl-CoA dehydrogenase
guish β oxidation in peroxisomes.
The peroxisomal flavoproteins that O
catalyze the dehydrogenation of
5
R
acyl-CoA molecules to unsaturated
S CoA
2
enoyl-CoAs (step b of Fig. 17-1) are
I
β Oxidation continued II
oxidases in which the FADH that is
2
d
formed is reoxidized by O to form
2 Enoyl-CoA
13,20 isomerase
H O . In peroxisomes the enoyl-
2 2 b
+ Acetyl-CoA O
hydratase and the NAD -dependent
dehydrogenase catalyzing steps c and O
R 5 3
d of Fig. 17-1 are present together S CoA
3
R
with an enoyl-CoA isomerase (next 3-trans-5-cis-Dienoyl-CoA
S CoA
section) as a trifunctional enzyme
3 2 e
∆ , ∆ -Enoyl-CoA
c
consisting of a single polypeptide isomerase From O
–
21 NADPH H
chain. As in mitochondrial β oxida-
O
tion the 3-hydroxyacyl-CoA inter-
R S CoA
4
mediates formed in both animal
R S CoA H+
peroxisomes and plant peroxisomes 2
(glyoxysomes) have the L configura- 2,4-Dienoyl-CoA reductase f
O
tion. However, in fungal peroxi-
3
somes as well as in E. coli they have
22,23
the D configuration. Further R S CoA
metabolism in these organisms
Enoyl-CoA isomerase g
requires an epimerase that converts
O
the D-hydroxyacyl-CoA molecules
24
to L. In the past it has often been
Complete β oxidation R S CoA
assumed that peroxisomal membranes 2
(17-1)
Ch 17IND page - E - 941 2/14/03, 11:15 AM
942 Chapter 17. The Organization of Metabolism
21 9
pathway is similar. However, the intermediate edible proteins.
formed in step e of Eq. 17-1 may sometimes have the 2- The first step in oxidation of alkanes is usually an
17
trans, 4-cis configuration. The NADH for the reduc- O -requiring hydroxylation (Chapter 18) to a primary
2
tive step f may be supplied by an NADP-dependent alcohol. Further oxidation of the alcohol to an acyl-CoA
29c
isocitrate dehydrogenase. Repetition of steps a, d, derivative, presumably via the aldehyde (Eq. 17-2), is a
e, and f of Eq. 17-1 will lead to β oxidation of the frequently encountered biochemical oxidation sequence.
entire chain of polyunsaturated fatty acids such as
linoleoyl-CoA or arachidonoyl-CoA. Important addi- O2
n-Octane C7H15 CH2 OH
tional metabolic routes for polyunsaturated fatty acid Hydroxylation
Octanol
derivatives are described in Chapter 21.
Branched-chain fatty acids. Most of the fatty C
7H15 CHO
acids in animal and plant fats have straight unbranched
chains. However, branches, usually consisting of
O
methyl groups, are present in lipids of some micro-
organisms, in waxes of plant surfaces, and also in C
7H15 C S CoA
polyprenyl chains. As long as there are not too many Acyl-CoA
(17-2)
branches and if they occur only in the even-numbered
positions (i.e., on carbons 2, 4, etc.) β oxidation proceeds
normally. Propionyl-CoA is formed in addition to Alpha oxidation and omega oxidation. Animal
acetyl-CoA as a product of the chain degradation. On tissues degrade such straight-chain fatty acids as
the other hand, if methyl groups occur in positions 3, palmitic acid, stearic acid, and oleic acid almost entirely
5, etc., β oxidation is blocked at step d of Fig. 17-1. A by β oxidation, but plant cells often oxidize fatty acids
striking example of the effect of such blockage was one carbon at a time. The initial attack may involve
hydroxylation on the α-carbon atom (Eq. 17-3) to
17,18,32,32a
form either the D- or the L-2-hydroxy acid. The
A CH3 branch here
blocks β oxidation L-hydroxy acids are oxidized rapidly, perhaps by dehy-
drogenation to the oxo acids (Eq. 17-3, step b) and
O
4 3 2 1 oxidative decarboxylation, possibly utilizing H2O2 (see
CH2 CH2 CH2 C S CoA
Eq. 15-36). The D-hydroxy acids tend to accumulate
A CH3 branch here
leads to formation R CH2
of propionyl-CoA –
COO
CoA–SH
d
a
O OH
provided by the synthetic detergents in common use R CH2
H
until about 1966. These detergents contained a hydro- C S CoA R C
–
carbon chain with methyl groups distributed more or COO
O
(2R), d-
less randomly along the chain. Beta oxidation was
O Fe2+
2
2-Oxoglutarate
blocked at many points and the result was a foamy
b Ascorbate
pollution crisis in sewage plants in the United States e
H
and in some other countries. Since 1966, only bio-
OH
H
degradable detergents having straight hydrocarbon R C
R C
chains have been sold. O
C S CoA
In fact, cells are able to deal with small amounts of
these hard-to-oxidize substrates. The O -dependent O
2
reactions called α oxidation and ω oxidation are used. (2S), l-
These are related also to the oxidation of hydrocarbons
Thiamin O O
c
which we will consider next. diphosphate
R C R C
–
H H O
Oxidation of saturated hydrocarbons. Although
C S CoA O
the initial oxidation step is chemically difficult, the
R C
tissues of our bodies are able to metabolize saturated
O
hydrocarbons such as n-heptane slowly, and some S CoA
microorganisms oxidize straight-chain hydrocarbons H–COOH
30,31
rapidly. Strains of Pseudomonas and of the yeast β Oxidation
Candida have been used to convert petroleum into
CO (17-3)
2
Ch 17IND page - E - 942 2/14/03, 11:15 AM
A. The Oxidation of Fatty Acids 943
and are normally present in green leaves. However, In plants α-dioxygenases (Chapter 18) convert
they too are oxidized further, with retention of the α free fatty acids into 2(R)-hydroperoxy derivatives (Eq.
32a
hydrogen as indicated by the shaded squares in Eq. 17-3, 7-3, step d). These may be decarboxylated to fatty
step e. This suggests a new type of dehydrogenation aldehydes (step e, see also Eq. 15-36) but may also give
with concurrent decarboxylation. Alpha oxidation also rise to a variety of other products. Compounds arising
occurs to some extent in animal tissues. For example, from linoleic and linolenic acids are numerous and
when β oxidation is blocked by the presence of a include epoxides, epoxy alcohols, dihydroxy acids,
methyl side chain, the body may use α oxidation to get short-chain aldehydes, divinyl ethers, and jasmonic
32a
past the block (see Refsum disease, Box 17-A). As in acid (Eq. 21-18).
33–35
plants, this occurs principally in the peroxisomes On other occasions, omega (␻) oxidation occurs
and is important for degradation not only of poly- at the opposite end of the chain to yield a dicarboxylic
prenyl chains but also bile acids. In the brain some of acid. Within the human body 3,6-dimethyloctanoic
the fatty acyl groups of sphingolipids are hydroxylated acid and other branched-chain acids are degraded largely
36
to α-hydroxyacyl groups. Alpha oxidation in animal via ω oxidation. The initial oxidative attack is by a
cells occurs after conversion of free fatty acids to their hydroxylase of the cytochrome P450 group (Chapter
acyl-CoA derivatives (Eq. 7-3, step a). This is followed 18). These enzymes act not only on fatty acids but also
by a 2-oxoglutarate-dependent hydroxylation (step b, on prostaglandins, sterols, and many other lipids. In
see also Eq. 18-51) to form the 2-hydroxyacyl-CoA, the animal body fatty acids are sometimes hydroxylated
which is cleaved in a standard thiamin diphosphate- both at the terminal (ω) position and at the next (ω-2 or
requiring α cleavage (step c). The products are formyl- ω2) carbon. In plants hydroxylation may occur at the
17,37
CoA, which is hydrolyzed and oxidized to CO , and ω2, ω3, and ω4 positions as well. Dicarboxylates
2
a fatty aldehyde which is metabolized further by β resulting from ω oxidation of straight-chain fatty acids
34a
oxidation.
BOX 17-A REFSUM DISEASE
Phytol is normally formed in the body (step a in the accom-
β Oxidation is blocked here
panying scheme) from the polyprenyl plant alcohol
a
phytol, which is found as an ester in the chloro-
CH3 CH3
O phyll present in the diet (Fig. 23-20). Although only
H ( CH2 CH CH2 CH2 ) CH2 CH CH2 C a small fraction of the ingested phytol is oxidized
3
Phytanic acid OH to phytanic acid, this acid accumulates to a certain
b α Oxidation (Eq. 17-3) extent in animal fats and is present in dairy products.
Because β oxidation is blocked, the first step (step b)
in degradation of phytanic acid is α oxidation in
CH3
O a
peroxisomes. The remainder of the molecule
R CH2 C C
undergoes β oxidation (step c) to three molecules
S CoA of propionyl-CoA, three of acetyl-CoA, and one of
H
isobutyryl-CoA. The disease, which was described
by Refsum in 1946, causes severe damage to nerves
c Degradation via β oxidation
and brain as well as lipid accumulation and early
b – d
O death. This rare disorder apparently results
from a defect in the initial hydroxylation. The
3 CH3 CH2 C
causes of the neurological symptoms of Refsum
S CoA
disease are not clear, but it is possible that the iso-
O
prenoid phytanic acid interferes with prenylation
+ 3 CH
3 C
b
of membrane proteins.
S CoA
O
a
Singh, I., Pahan, K., Dhaunsi, G. S., Lazo, O., and Ozand, P.
+ CH
3 CH C (1993) J. Biol. Chem. 268, 9972 – 9979
b
Steinberg, D. (1995) in The Metabolic and Molecular Bases of
S CoA
CH3 Inherited Disease, 7th ed., Vol. 2 (Scriver, C. R., Beaudet, A. L.,
Sly, W. S., and Valle, D., eds), pp. 2351 – 2369, McGraw-Hill,
New York
c
Steinberg, D., Herndon, J. H., Jr., Uhlendorf, B. W., Mize, C. E.,
In this autosomally inherited disorder of lipid
Avigan, J., and Milne, G. W. A. (1967) Science 156, 1740 – 1742
metabolism the 20-carbon branched-chain fatty acid d
Muralidharan, V. B., and Kishimoto, Y. (1984) J. Biol. Chem. 259,
phytanic acid accumulates in tissues. Phytanic acid 13021 – 13026
Ch 17IND page - E - 943 2/14/03, 11:15 AM
944 Chapter 17. The Organization of Metabolism
can undergo β oxidation from both ends. The resulting O
short-chain dicarboxylates, which appear to be formed
R C S CoA
38
primarily in the peroxisomes, may be converted by
Acyl-CoA
further β oxidation into succinyl-CoA and free succi-
39
nate. Incomplete β oxidation in mitochondria (Fig. Carnitine
17-1) releases small amounts of 3(β)-hydroxy fatty Acyltransferase
acids, which also undergo ω oxidation and give rise CoA SH
to free 3-hydroxydicarboxylic acids which may be
40 O CH3
excreted in the urine.
N CH3
R C O +
CH3
–
2. Carnitine and Mitochondrial Permeability O
H
C
A major factor controlling the oxidation of fatty
O
Acyl carnitine (17-4)
acids is the rate of entry into the mitochondria. While
some long-chain fatty acids (perhaps 30% of the total)
enter mitochondria as such and are converted to CoA
derivatives in the matrix, the majority are “activated” Thus, carnitine may have a regulatory function. In
to acyl-CoA derivatives on the inner surface of the flight muscles of insects acetylcarnitine serves as a
outer membranes of the mitochondria. Penetration of reservoir for acetyl groups. Carnitine acyltransferases
these acyl-CoA derivatives through the mitochondrial that act on short-chain acyl-CoA molecules are also
41–44
inner membrane is facilitated by L-carnitine. present in peroxisomes and microsomes, suggesting
that carnitine may assist in transferring acetyl groups
and other short acyl groups between cell compartments.
H3C For example, acetyl groups from peroxisomal β oxida-
+
–
N COO tion can be transferred into mitochondria where they
H3C
can be oxidized in the citric acid cycle.41
H OH
CH3
l-Carnitine
3. Human Disorders of Fatty Acid Oxidation
Carnitine is present in nearly all organisms and in
all animal tissues. The highest concentration is found Mitochondrial β oxidation of fatty acids is the
in muscle where it accounts for almost 0.1% of the dry principal source of energy for the heart. Consequently,
matter. Carnitine was first isolated from meat extracts inherited defects of fatty acid oxidation or of carnitine-
in 1905 but the first clue to its biological action was assisted transport often appear as serious heart disease
obtained in 1948 when Fraenkel and associates described (inherited cardiomyopathy). These may involve heart
a new dietary factor required by the mealworm, Tenebrio failure, pulmonary edema, or sudden infant death.
molitor. At first designated vitamin B , it was identified As many as 1 in 10,000 persons may inherit such prob-
t
48–50a
in 1952 as carnitine. Most organisms synthesize their lems. The proteins that may be defective include
own carnitine from lysine side chains (Eq. 24-30). a plasma membrane carnitine transporter; carnitine
The inner membrane of mitochondria contains a long- palmitoyltransferases; carnitine/acylcarnitine trans-
chain acyltransferase (carnitine palmitoyltransferase I) locase; long-chain, medium-chain, and short-chain
that catalyzes transfer of the fatty acyl group from acyl-CoA dehydrogenases; 2,4-dienoyl-CoA reductase
45–47a
CoA to the hydroxyl group of carnitine (Eq. 17-4). (Eq. 17-1); and long-chain 3-hydroxyacyl-CoA dehydro-
Perhaps acyl carnitine derivatives pass through the genase. Some of these are indicated in Fig. 17-2.
membrane more easily than do acyl-CoA derivatives Several cases of genetically transmitted carnitine
because the positive and negative charges can swing deficiency in children have been recorded. These
together and neutralize each other as shown in Eq. 17-4. children have weak muscles and their mitochondria
Inside the mitochondrion the acyl group is transferred oxidize long-chain fatty acids slowly. If the inner
back from carnitine onto CoA (Eq. 17-4, reverse) by mitochondrial membrane carnitine palmitoyltrans-
carnitine palmitoyltransferase II prior to initiation of ferase II is lacking, long-chain acylcarnitines accumu-
β oxidation. late in the mitochondria and appear to have damaging
Tissues contain not only long-chain acylcarnitines effects on membranes. In the unrelated condition of
but also acetylcarnitine and other short-chain acylcar- acute myocardial ischemia (lack of oxygen, e.g.,
41
nitines, some with branched chains. By accepting during a heart attack) there is also a large accumulation
51,52
acetyl groups from acetyl-CoA, carnitine causes the of long-chain acylcarnitines. These compounds may
release of free coenzyme A which can then be reused. induce cardiac arrhythmia and may also account for
Ch 17IND page - E - 944 2/14/03, 11:15 AM