Download Chem*3560 Lecture 22: Fatty acid desaturation Relationship of

Chem*3560 Lecture 22:
Fatty acid desaturation
Relationship of carbohydrate and fatty acid metabolism
The fatty acid synthase multienzyme complex converts
cytoplasmic acetyl CoA and malonyl CoA into the C16
fatty acid, palmitate. Most animal fats and
phospholipids lipids contain more C18 fatty acid such as
stearate, while lipids in the nervous system can contain
chains of C24 (nervonic acid) or longer. Additional
elongation is carried out by the fatty acid elongase
system.
Elongase is a set of four more loosely associated
enzymes on the endoplasmic reticulum membrane that
act on acyl-CoA derivatives rather than acyl-ACP
(Lehninger p.781). The individual enzymes make the
elongation process less efficient than the fatty acid
synthase complex.
Fatty acid desaturation
The other modification of fatty acid involves
introduction of cis-double bonds. The double bonds
introduced by dehydratase are trans-, so can't simply
be left in place.
Lipids that include unsaturated fatty acids with
cis-double bonds have lower the melting points. In
plants, unsaturated triacylglycerols are liquid oils rather
that solid fats like animal triacylglycerols, which are
predominantly made from saturated fatty acids. In
animals, unsaturated fatty acids are used mostly in the
phospholipids that make up membranes, and give the
phospholipids the necessary degree of fluidity.
Fatty acid desaturases belong to an unusual group of enzymes called mixed function oxidases.
The term oxidase indicates that molecular O2 is the electron acceptor. However, removing 2 H• atoms
from a substrate only consumes one of the two O atoms. To prevent the second O atom from making
dangerous peroxides, a reducing agent such as NADPH is used to reduce the second O atom safely to
H2 O. The term mixed function refers to the fact that each O atom of O2 takes a different reaction
pathway (Lehninger p.781).
The fatty acyl-CoA desaturase complex
Fatty acid desaturase is a multienzyme complex containing the following components:
The 9-desaturase is the substrate specific component that accepts a saturated 16 or 18 carbon
acyl-CoA, and removes 2 H atoms to create a cis-double bond between C-9 and C-10 (i.e.
bond 9 in the chain). The H atoms form H2 O using one of the O atoms of O2 . The other O
atom is made safe by reduction using 2 electrons, one each from 2 molecules of cytochrome b5
Fe 2+. Cytochrome b5 is an electron carrier related to cytochromes in mitochondrial electron
transport, but has a specific role in desaturation reactions.
Cytochrome b5 reductase recycles cytochrome b5 Fe 3+ back to the Fe2+ state. NADPH
serves as the final reducing agent, and passes two electrons to an internally bound FAD, making
FADH2 , and FADH2 reduces the cytochromes. Cytochrome b5 reductase is present in
several desaturase complexes.
A notation to describe unsaturated fatty acids
The 9-desaturation product from the C18 fatty acid stearoyl-CoA is oleyl-CoA. Many of the possible
unsaturated fatty acid have unique names, but a shorthand descriptive notation that describes fatty
structures in an unambiguous way is often used (Lehninger p.781):
oleate
=
18:1 (∆
∆ 9)
~
number of C
atoms in chain
„
„
location of the double bonds (cis unless otherwise specified)
number
of double bonds
Essential fatty acids in the diet
Animals also possess a fatty acid 5/6-desaturase, but lack desaturase for higher numbered positions.
The fatty acid arachidonate, 20:4 (∆
∆ 5, 8, 11, 14) is specifically required as precursor for an important
class of cellular signalling molecules called
prostaglandins.
Prostaglandins and other eicosanoids (from Greek
icosa, 20) regulate contraction of smooth or
involuntary muscles in bronchial passages, gut, and
blood vessel walls, and a subgroup are involved in
platelet activation (see Lehninger p.784-788 for
interest, but they fall outside the scope of this course).
In order to make arachidonate, animals must consume linoleate, 18:2 (∆
∆ 9, 12) or α -linolenate ,
18:3(∆
∆ 9, 12, 15), which are present in plant materials and vegetable oils (so called polyunsaturated
fatty acids ). Only plants possess the 12-desaturase and 15-desaturase enzymes, which act on
esterified fatty acids in phospholipids (Lehninger p.782-784).
When animals consume linoleate, their own enzymes can convert it to arachidonate in stepwise manner
(Lehninger fig. 21-13)
5/6-desaturase
elongase system
5/6-desaturase
linoleate
→
γ -linolenate →
eicosatrienoate
→
arachidonate
18:3(∆
∆ 6, 9, 12)
18:3(∆
∆ 6, 9, 12)
20:3(∆
∆ 8, 11, 14)
20:4(∆
∆ 5, 8, 11, 14)
α -linolenate
Double bonds produced by the desaturases are allylic, not conjugated. This means there is a single
-CH2 - between sets of double bonded C atoms, and double bonds are spaced 3 apart. Any -CH2 adjacent to a double bond is called an allylic carbon, and is unusually reactive towards O2 .
Paints used to be made from linseed oil, which is rich in linoleate and linolenate. O2 reacts with and
cross-links allylic C atoms in adjacent chains, so that the oil dries to a tough polymeric solid.
Relationship between carbohydrate and fat metabolism
In animals, there is no way to convert fats to sugars, since acetyl-CoA cannot be converted back into
pyruvate. Fats can only be consumed for energy metabolism, and if energy metabolism consumes less
fat that is produced, fat accumulates.
On the other hand, sugars and other carbohydrates are easily converted to fat. A sugar or starch rich
meal results in a large increase in blood glucose as the sugars are taken up by the digestive system.High
blood glucose triggers insulin release, which stimulates cells to take up glucose from the blood. In
peripheral tissues, glucose must be converted to glucose-6-phosphate by hexokinase. If
glucose-6-phosphate exceeds requirments, because ATP demand is low and glycogen levels are
already high, glucose-6-phosphate blocks further hexokinase activity by the product inhibition
effect.
Liver cells contain glucokinase or hexokinase D, which is the high KM isozyme and is unaffected by
product inhibition. As a result, liver continues to incorporate glucose from the blood. Insulin also
stimulates glycolysis in the liver, so that once glycogen levels are high, surplus glucose undergoes
glycolysis. Pyuvate is converted to acetyl CoA and citrate. If the [ATP] / [ADP] ratio is high, isocitrate
dehydrogenase activity will be low, so citrate spills over into the cytoplasm, and sets off the fatty acid
biosynthesis process.
Unused palmitoyl-CoA exerts end-product regulation of acetyl-CoA carboxylase, slowing down fatty
acid biosynthesis. Unforunately this results in accumulation of excess cytoplasmic acetyl CoA, and that
in turn becomes directed to the cholesterol biosynthesis pathway (for your interest, see Lehninger
p.799-805, but the topic lies outside the scope of this course).