Download Chem*3560 Lecture 35: Integration of metabolism in animals

Chem*3560
Lecture 35: Integration of metabolism in animals
Metabolism in complex organisms is tissue specific, especially in animals. Different organs of the body
play specialized roles in metabolism (lehninger p.869).
The gastrointestinal system breaks down the macromolecular components of food. Only small
molecules are readily taken up by epithelial cells of the gut.
Proteins break down to small peptides and amino acids; amino acids enter blood.
Starch breaks down to glucose (ruminants rely on gastrointestinal microorganisms to break
down cellulose); glucose enters blood.
Fats break down to fatty acids and monoacylglycerol; resynthesized to triacylglycerol and
distributed partly to the liver via blood
and partly to adipose tissue via
lymphatic system.
Liver metabolism is at the centre
To meet varying requirements of peripheral
tissues, the liver acts as the processing centre
and maintains the balance of carbohydrate
versus fat versus amino acid. Omnivorous
organisms (e.g. humans) must deal with varying
input of nutrients, so the liver must be highly
adaptable. The ability to adapt is the reason for
tight regulation of different pathways.
When glucose levels in blood are high,
glucose is taken up in liver very efficiently by the
GluT2 transporter (Lehninger p.870), which
remains active even under the influence of insulin.
The enzyme glucokinase or hexokinase D
functions well in high glucose, so that
glucose-6-phosphate levels easily exceed the
needs of catabolic reactions. Excess citrate
passes into the cytoplasm, supplying cytoplasmic
acetyl-CoA for synthesis of fatty acids and
cholesterol. Insulin maintains the activity of glycogen synthase, and this allows the liver’s glycogen
reserves to build up.
Liver maintains blood glucose levels
Low blood glucose causes the pancreas to
release the hormone glucagon, and liver
contains G-protein coupled receptors for
glucagon that stimulate adenylate cyclase,
activating the protein kinase cascade.
In liver, the protein kinase cascade activates
glycogen breakdown, as well as the liver
isozyme of the fructose-2,6-bisphosphate
bifunctional enzyme. In liver, the
fructose-2,6-bisphosphatase is activated by
phosphorylation, and this promotes
gluconeogenesis. Both sources provide glucose
to replenish the levels in blood.
Since gluconeogenesis depletes TCA cycle of
intermediates, conditions do not allow citrate
export from mitochondria, so fatty acid synthesis
is relatively inactive.
This also reduces the demand for NADPH, so
the pentose phosphate pathway is
relatively inactive.
Substrate for
gluconeogenesis comes
from amino acid oxidation
Amino acids in blood may be
derived from dietary protein. If this
source is insufficient, breakdown of
tissue proteins occurs, mostly from
body muscle mass (which is why
starvation dieting is ill-advised).
The liver has very active protein
synthesis and degradation, and also
makes plasma proteins to be
secreted into the blood.
Any excess amino acid then becomes available for gluconeogenesis. 18 out of the 20 amino acids make
at least a part of their carbon skeleton available either as pyruvate or as TCA cycle intermediates such
as succinate, fumarate or oxaloacetate (Lehninger p. 872).
Dietary fats are used for energy or to make more lipids
Dietary lipids represent the major
source of substrate for energy
production in the liver, by
β-oxidation and the TCA cycle
(except when blood glucose is high
and fatty acid biosynthesis occurs).
Fatty acids may be released into the
blood as free fatty acid, which is
consumed as an energy substrate by
muscles.
In animals, all acetyl CoA that enters
the TCA cycle is converted to CO2 ,
and it is not possible to use acetyl
CoA to produce surplus TCA cycle
intermediates or pyruvate.
Therefore lipids and fatty acids can't serve as a substrate for gluconeogenesis in animals. (This is
not the case in plants and bacteria, which possess a non-oxidative bypass for the TCA cycle called the
glyoxylate cycle.) Acetyl-CoA can act as a precursor for cholesterol biosynthesis. Triacylglycerols,
cholesterol and excess phospholipids are exported from liver to other tissues in the form of plasma
lipoproteins.
The liver also exports products of acetyl CoA condensation called ketone bodies. Ketone bodies
build up when large amounts of acetyl CoA accumulate, so that the liver cell is short of HSCoA.
HSCoA is liberated by reversal of the thiolase reaction of β-oxidation:
CH3 CO-SCoA
‡
normal direction in β-oxidation
←
direction with high [acetyl CoA] and low [HSCoA]
→
CH3 CO-SCoA
+
CH3 COCH2 CO-SCoA + HSCoA
acetoacetyl-CoA
The major ketone body is actually β-hydroxybutyrate, derived by reduction of acetoacetate, and
represents a water soluble, exportable product of acetyl CoA. The heart and other muscles can use
β-hydroxybutyrate as an energy source rather than consuming glucose (Lehninger p.873).
Specialized tissues
Adipose tissue: stores fatty acid as triacylglycerol, either by taking up dietary triacylglycerol directly,
or by utilization of excess blood glucose. Insulin stimulates glucose use.
Muscles: use substrates for energy metabolism; ATP is used for mechanical work. Muscle fibres can
exist in two forms: fast twitch and slow twitch. The proportion of fast twitch cells is a muscle is a
function of training. Weight-lifters and sprinters
develop fast twitch. Endurance activities develop
slow twitch cells.
Fast twitch cells store glycogen, and use anaerobic
glycolysis to generate ATP. The lactate produced is
circulated in the blood for the liver to regenerate by
gluconeogenesis. The rate of ATP production can be
100 × faster than aerobic metabolism, but consumes
glucose very rapidly.
Slow twitch cells are rich in mitochondria and use
aerobic metabolism of glucose, fatty acids and
β-hydroxybutyrate.
Muscle cells contain high levels (10-30 mM) of creatine phosphate to act as a buffer for ATP
production (Lehninger p. 875).
creatine kinase
creatine + ATP ‡ creatine phosphate + ADP
→ direction during relative physical inactivity
← direction during intense bursts of activity
There is constant physical damage and repair of muscle fibres especially during vigorous activity.
Repair enlarges and generates stronger muscles, and is the basis of body building. Because this involves
very active protein degradation and resynthesis, qamino acids can be withdrawn from the muscle when
other nutrients are in short supply.
Brain and nervous system: use primarily aerobic glucose metabolism for energy metabolism; ATP
is required to maintain the ion gradients of Na+, K+ and Ca2+ generated by various ion pumps (e.g. Na+
/K + ATPase). This requires a steady supply of glucose and O2 for proper function (see Lehninger
p.878, Fig. 23-11 for the consequences of low blood glucose). It is the function of the liver, in
response to release of the hormone glucagon, to ensure that blood glucose leveles are maintained by
gluconeogenesis. After 2-3 days fasting, the brain modifies its metabolism to allow use
β-hydroxybutyrate as an alternative to glucose. This reduces the demand on muscle protein to provide
substrate for gluconeogenesis.