Overview of Metabolism & the Provision of Metabolic Fuels

Metabolism is the term used to describe the interconversion of chemical

compounds in the body, the pathways taken by individual molecules, their
interrelationships, and the mechanisms that regulate the flow of metabolites
through the pathways.
Metabolic pathways fall into three categories.
(1) Anabolic pathways, which are those involved in the synthesis of larger and
more complex compounds from smaller precursors (for example, the synthesis of
protein from amino acids and the synthesis of reserves of triacylglycerol and
glycogen). Anabolic pathways are endothermic.
(2) Catabolic pathways, which are involved in the breakdown of larger molecules,
commonly involving oxidative reactions; they are exothermic, producing reducing
equivalents, and, mainly via the respiratory chain, ATP.
(3) Amphibolic pathways, which occur at the “crossroads” of metabolism, acting
as links between the anabolic and catabolic pathways, for example, the citric acid
cycle.
Knowledge of normal metabolism is essential for an understanding of
abnormalities that underlie a disease. Normal metabolism includes adaptation to
periods of fasting, starvation, and exercise, as well as pregnancy and lactation.
Abnormal metabolism may result from nutritional deficiency, enzyme deficiency,
abnormal secretion of hormones, or the actions of drugs and toxins.
A 70-kg adult human being requires about 1920-2900 kcal from metabolic fuels
each day, depending on physical activity. Growing children have a proportionally
higher requirement to allow for the energy cost of growth. For human beings, this
energy requirement is met from carbohydrates (40%-60%), lipids (mainly
triacylglycerol, 30%-40%), and protein (10%-15%), as well as alcohol. The mix of
carbohydrate, lipid, and protein being oxidized varies, depending on whether the
subject is in the fed or fasting state, and on the duration and intensity of physical
work.
There is a constant requirement for metabolic fuels throughout the day. However,
most people consume their daily intake of metabolic fuels in two or three meals, so
there is a need to form reserves of carbohydrate (glycogen in liver and muscle),
lipid (triacylglycerol in adipose tissue), and proteins stores during the period
Dr. Ali A. Kasim/ College of Pharmacy/ University of Baghdad
following a meal, for use during the intervening time when there is no intake of
food.
If the intake of metabolic fuels is consistently greater than energy expenditure, the
excess is stored, largely as triacylglycerol in adipose tissue, leading to the
development of obesity and its associated health hazards. By contrast, if the intake
of metabolic fuels is consistently lower than energy expenditure, there are
negligible reserves of fat and carbohydrate, and amino acids arising from protein
turnover are used for energy-yielding metabolism rather than replacement protein
synthesis, leading to emaciation, wasting, and, eventually, death.
In the fed state, after a meal, there is a plentiful supply of carbohydrate, and the
metabolic fuel for most tissues is glucose. In the fasting state, glucose must be
spared for use by the central nervous system (which is largely dependent on
glucose) and the red blood cells (which are wholly dependent on glucose).
Therefore, tissues that can use fuels other than glucose do so; muscle and liver
oxidize fatty acids and the liver synthesizes ketone bodies from fatty acids to
export to muscle and other tissues. As glycogen reserves become depleted, amino
acids arising from protein turnover are used for gluconeogenesis (and ketogenesis).
The formation and utilization of reserves of triacylglycerol and glycogen, and the
extent to which tissues take up and oxidize glucose, are largely controlled by the
hormones insulin and glucagon. In diabetes mellitus, there is either impaired
synthesis and secretion of insulin (type I diabetes, previously known as juvenile
onset, or insulin-dependent diabetes) or impaired sensitivity of tissues to insulin
action (type II diabetes, sometimes called adult onset or noninsulin-dependent
diabetes), leading to severe metabolic derangement.
Levels of organization of metabolic pathways
In addition to studies in the whole organism, the location and integration of
metabolic pathways is revealed by studies at two levels of organization. At the
tissue and organ level, the nature of the substrates entering and metabolites
leaving tissues and organs can be measured. At the subcellular level, each cell
organelle (eg, the mitochondrion) or compartment (eg, the cytosol) has specific
roles that form part of a subcellular pattern of metabolic pathways.
At the Tissue & Organ Level
Products of digestion (amino acids, glucose and triacylglycerol) are absorbed via
the hepatic portal vein.
Dr. Ali A. Kasim/ College of Pharmacy/ University of Baghdad
Liver
Taking up glucose in excess of immediate requirements and using it to synthesize
glycogen (glycogenesis) or fatty acids (lipogenesis).
Between meals, the liver acts to maintain the blood glucose concentration by
breaking down glycogen (glycogenolysis) and, together with the kidney, by
converting noncarbohydrate metabolites such as lactate, glycerol, and amino acids
to glucose (gluconeogenesis).
Partial oxidation of fatty acids in the liver leads to ketone body production
(ketogenesis). Ketone bodies are exported to extrahepatic tissues, where they
provide a fuel in prolonged fasting and starvation.
The liver also synthesizes the major plasma proteins (eg, albumin) and
deaminates amino acids that are in excess of requirements, synthesizing urea,
which is transported to the kidney and excreted.
Note: Unlike glucose and amino acids absorbed from the small intestine,
triacylglycerol is not taken up directly by the liver. It is first metabolized by tissues
that have lipoprotein lipase, which hydrolyzes the triacylglycerol, releasing fatty
acids that are incorporated into tissue lipids or oxidized as fuel. The remnants are
cleared by the liver.
Skeletal muscle
It stores glycogen (glycogenesis) as a fuel for use in muscle contraction during
prolong fasting or starvation (glycogenolysis).
It synthesizes muscle protein from plasma amino acids. Muscle accounts for
approximately 50% of body mass and consequently represents a considerable store
of protein that can be drawn upon to supply amino acids for gluconeogenesis in
starvation.
Adipose tissue
Triacylglycerol is the main fuel reserve of the body. It is hydrolyzed (lipolysis) and
glycerol and non-esterified (free) fatty acids are released into the circulation.
Glycerol is a substrate for gluconeogenesis. The fatty acids are transported bound
to serum albumin; they are taken up by most tissues (but not brain or erythrocytes)
and either esterified to triacylglycerols for storage or oxidized as a fuel.

Dr. Ali A. Kasim/ College of Pharmacy/ University of Baghdad

At the Subcellular Level
Compartmentation of pathways in separate subcellular compartments or organelles
permits integration and regulation of metabolism. Not all pathways are of equal
importance in all cells.
Pathways occurring in the mitochondria
The citric acid cycle, β-oxidation of fatty acids, ketogenesis, as well as the
respiratory chain and ATP synthase.
Pathways occurring in the cytosol
Glycolysis, the pentose phosphate pathway, and fatty acid synthesis.
Pathways with some reactions occurring in the cytosol and others in the
mitochondria
Gluconeogenesis and urea cycle
Pathway occurring in the membranes of the endoplasmic reticulum
Triacylglycerol synthesis
Pathway occurring the ribosomes
Protein synthesis

Regulation of the Flux of Metabolites through Metabolic Pathways

In a reaction at equilibrium, the forward and reverse reactions occur at equal rates,
and there is therefore no net flux in either direction. In practice, there are normally
one or more nonequilibrium reactions in a metabolic pathway. The enzymes
catalyzing nonequilibrium reactions are usually present in low concentration and
are subject to a variety of regulatory mechanisms.
Note: most reactions in metabolic pathways cannot be classified as equilibrium or
nonequilibrium, but fall somewhere between the two extremes.
The flux-generating reaction can be identified as a nonequilibrium reaction in
which the Km of the enzyme is considerably lower than the normal concentration of
substrate. The first reaction in glycolysis, catalyzed by hexokinase, is such a flux-
generating step because its Km for glucose of 0.05 mmol/L is well below the
normal blood glucose concentration of 3 to 5 mmol/L.

Dr. Ali A. Kasim/ College of Pharmacy/ University of Baghdad

Factors regulating the flux of metabolites through metabolic pathways
The flux through this pathway can be regulated by the availability of the initial
substrate. This depends on its supply from the blood, which in turn depends on
either food intake or key reactions that release substrates from tissue reserves into
the bloodstream, for example, glycogenolysis in liver and lipolysis in adipose
tissue. It also depends on the transport of the initial substrate into the cell. Muscle
and adipose tissue only take up glucose from the bloodstream in response to the
hormone insulin.
Flux is also determined by removal of the end product and the availability of
cosubstrates or cofactors. Enzymes catalyzing nonequilibrium reactions are often
allosteric proteins subject to the rapid actions of “feed-back” or “feed-forward”
control by allosteric modifiers, in immediate response to the needs of the cell.
Frequently, the end product of a biosynthetic pathway inhibits the enzyme
catalyzing the first reaction in the pathway.
Other control mechanisms depend on the action of hormones responding to the
needs of the body as a whole; they may act rapidly by altering the activity of
existing enzyme molecules, or slowly by altering the rate of enzyme synthesis.

Many Metabolic Fuels are Interconvertible

There is a need to process the products of
digestion of dietary carbohydrate, lipid, and
protein; these are mainly glucose, fatty acids
and glycerol, and amino acids, respectively.
All the products of digestion are
metabolized to a common product, acetyl-
CoA, which is then oxidized by the citric
acid cycle.
End products (or intermediate product) of a
given metabolic pathway can be utilized as
a substrate of another. Acetyl-CoA for
example can be used interchangeably
among many pathways.
Gluconeogenesis utilizes products from
lipolysis and from amino acid catabolism.

Dr. Ali A. Kasim/ College of Pharmacy/ University of Baghdad

CLINICAL ASPECTS
In prolonged starvation, as adipose tissue reserves are depleted, there is a very
considerable increase in the net rate of protein catabolism to provide amino acids,
as substrates for gluconeogenesis. Death results when essential tissue proteins are
catabolized and not replaced. In patients with cachexia as a result of release of
cytokines in response to tumors and disease, there is an increase in the rate of
tissue protein catabolism, as well as a considerably increased metabolic rate, so
they are in a state of advanced starvation. Again, death results when essential tissue
proteins are catabolized and not replaced.
In pregnancy and lactation, the high demand for glucose by the fetus, and for
lactose synthesis in lactation, can lead to ketosis. This may be seen as mild ketosis
with hypoglycemia in human beings.
In poorly controlled type 1 diabetes mellitus, patients may become hyperglycemic,
both as a result of lack of insulin to stimulate uptake and utilization of glucose, and
because in the absence of insulin to antagonize the actions of glucagon, there is
increased gluconeogenesis from amino acids in the liver. At the same time, the lack
of insulin to antagonize the actions of glucagon results in increased lipolysis in
adipose tissue, and the resultant nonesterified fatty acids are substrates for
ketogenesis in the liver.
In uncontrolled diabetes, the ketosis may be severe enough to result in pronounced
acidosis (ketoacidosis); acetoacetate and 3-hydroxybutyrate are relatively strong
acids.
Coma results from both the acidosis and also the considerably increased osmolality
of extracellular fluid (mainly as a result of the hyperglycemia, and diuresis
resulting from the excretion of glucose and ketone bodies in the urine).

Dr. Ali A. Kasim/ College of Pharmacy/ University of Baghdad