Organic chemistry and Biological chemistry for Health Sciences
59-191
Lecture 24
Gluconeogenesis is not just the reverse of glycolysis. Three of the steps in glycolysis
namely steps 1, 3, and 10 cannot be directly reversed. Special enzymes exist in the liver
and the kidneys that create bypasses around these irreversable steps.
In the bypass that gets around step 10 of glycolysis, the synthesis of phosphoenolpyruvate
from pyruvate, bicarbonate ion is used as a reactant. It is the source of CO 2 that becomes
inserted into pyruvate. The energy of ATP is used to drive the synthesis and pyruvate
carboxylase is the enzyme. Pyruvate is changed to oxaloacetate. This reaction occurs in
mitochondria but gluconeogenesis that uses this product, oxaloacetate, occurs in cytosol.
After a complex shuttle mechanism oxaloacetate gets through the mitochondrial
membranes, it reacts in the cytosol with another triphophate, guanosine triphosphate, as
carbon dioxide splits out and bonds rearrange to form phosphoenolpyruvate. Because
synthesis of one glucose requires two pyruvate, and because each pyruvate requires two
high energy phosphates in gluconeogenesis, this bypass cost the equivalent of four ATPs
(2ATP + 2GTP) per glucose molecule. At the reversal of step 7, two more ATPs are used
per molecule glucose made. Thus a total of six ATPs are required to make one glucose
molecule by gluconeogenesis, starting from pyruvate. The bypasses to the reverse of step
3 and 1 of glycolysis requires only specific enzymes that catalyze the hydrolysis of
phosphate ester groups.
METABOLISM OF LIPIDS:
The digestion of triacylglycerols produces a mixture of the anions of fatty acids,
monoacylglycerol and some diacylglycerol. In the intestinal membrane they are
reconverted to triacylglycerols. Triacylglycerol and dietary cholesterol, make up most of
the exogenous lipid material delivered to circulation.
Lipids are virtually insoluble in water, which creates a problem for transport in blood.
The body combines them with protein so they can be transported as tiny particles, more
easily dispersed in blood, called lipoprotein complexes. There are several kinds
classified according to their densities.
Lipoprotein complexes with the lowest density have only 2% protein or less and are
called chilomacrons.
They are put together from exogenous lipids within the
cells of intestinal membrane and delivered to the lymph, which carries them to the
bloodstream. When in the capillaries of muscle and adipose tissue, chilomicrons are
detained by binding sites where an enzyme lipoprotein lipase, hydrolyzes their
triacylglycerols to fatty acids and monoacylglycerols. The nearby tissue promptly absorbs
these. Left over is chylomicron remnants. The chylomicron remnant, which still contains
dietary cholesterol, leaves the capillary surfaces and circulates to the liver, where they are
absorbed. The role of chylomicrons is thus to take exogenous fatty acids to muscle and
adipose tissue and dietary cholesterol to the liver.
The liver makes fatty acids and then triacylglycerol from carbohydrates. Lipids made in
the liver are endogenous lipids. Three similar lipoprotein complexes are used to
transport endogenous lipids in the bloodstream, namely very low density lipoprotein
(VLDL), intermediate density lipoprotein (IDL), and low density lipoproteins (LDL). All
three carry cholesterol, especially the LDL. Another lipoprotein complex, high-density
lipoprotein (HDL), carries cholesterol released from the tissues, no longer needed by
them, and ready for being exported via the bile.
The liver packages triacylglycerols and cholesterol into VLDL and releases them into
circulation. In circulation, VLDL undergoes continuous changes as its triacylglycerols are
hydrolyzed in capillaries, thus delivering fatty acids to adipose tissue and muscle. By
these processes, the net density increases and so VLDL particle change to IDL.
With continued loss of low-density triacylglycerol, the IDL change to LDL. The liver
reabsorbs some LDL, but the main purpose of LDL is to deliver cholesterol to
extrahepatic tissue to be used to make cell membrane and in specialized tissues, steroid
hormone. LDL carries more cholesterol in the bloodstream than any other particle.
High-density lipoprotein complexes, HDL, are cholesterol scavangers. When cells of
extrahepatic tissue break down, their cholesterol molecules are picked up by HDL
particles and changed to cholesteryl ester. HDL transfers some cholesteryl ester to the
adrenal glands and the ovaries to make steroid hormones from cholesterol. Some HDL
become more like LDL before entering liver cells through the LDL receptors.
Fatty acids are mainly stored in adipose tissue. Some tissues like heart muscle and the
renal cortex, use breakdown products of fatty acids in preference to glucose for energy.
Skeletal muscles can use both fatty acids and short molecules made from them for
energy. In fact most of the energy needs of resting muscle tissue are met by intermediates
of fatty acid catabolism, not from glucose. Adipose tissue is associated with internal
organs, where they cushion the organs against mechanical bumps and shocks and
insulates them from swings in temperature.
Fatty acid come and go from adipose tissue, and the balance between the tissues
receiving or releasing them is struck by the energy requirements elsewhere. In extreme
distress, either very low in supply or what is available cannot be used, the body must turn
almost entirely to its fatty acids for energy.
Triacylglycerol molecules are first hydrolyzed to free fatty acids and glycerol, the lipase
being activated by epinephrine and cyclic AMP. The fatty acids are carried as albumin
complexes to the liver, the chief site for their catabolism.
Insulin suppresses the lipase that releases fatty acids from adipose tissue. Thus when
insulin is in circulation, and its presence is linked to the presence of blood glucose, the
fatty acids are less required for energy.
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Oxidation of fatty acids:
The degradation of fatty acids takes place inside mitochondria by a repeating series of
steps known as -oxidation pathway. The -oxidation pathway occurs in the
mitochondrial matrix, but before a fatty acid can enter -oxidation, has to be joined to
coenzyme A in the cytosol. The fatty acyl unit of fatty acyl CoA is passed through the
mitochondrial membrane to be joined inside to coenzyme A. This sequesters the fatty
acyl unit in a place of catabolism, not anabolism.
The repeating sequence of -oxidation consists of four steps. One turn of the sequence is
used to make one molecule of FADH2, one of NADH, one of acetyl coenzyme A, and a
fatty acyl unit with two fewer carbons. The shortened fatty acyl unit goes through the
four steps again, and the process is repeated until no more two-carbon acetyl units can be
made.
The FADH2 and NADH produced by -oxidation fuel the respiratory chain directly. The
acetyl groups fuel the respiratory chain indirectly passing through the citric acid cycle, or
they enter the general pool of acetyl coenzyme A that the body uses to make other
substances, like cholesterol.
-oxidation pathway consists of four steps written below:
1. In the first step, dehydrogenation produces a double bond between - and -carbon
atoms. The enzyme responsible for this first step, acyl CoA dehydrogenase, includes
FAD as a prosthetic group. The electrons removed from the fatty acyl CoA are
transferred to the FAD to convert it to FADH2. FADH2 delivers the electrons to the
respiratory chain.
2. In the second step of fatty acid oxidation water adds to an alkene double bond, and a 20
alcohol forms. This reaction is catalyzed by enoyl-CoA hydratase.
3. The 20 alcohol is dehydrogenated (oxidized) to a keto group. These three steps
accomplish the oxidation of the -position of the fatty acyl group to a keto group.
This is why the pathway is called -oxidation. The purpose is to weaken the C-2 to C-3
bond, setting it up for being broken, next.
4. The fourth and last step of the fatty acid oxidation cycle is catalyzed by -ketoacylCoA thiolase. The bond between the -carbon and -carbon now breaks. The remaining
acyl unit, original shortened by two carbons, now goes through the cycle of steps again:
dehydrogenation, hydration, dehydrogenation, and bond cleavage. After seven cycles,
one molecule of palmitoyl CoA is broken into eight molecules of acetyl CoA.
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