The World Turned Upside Down: The Second Low-Carbohydrate Revolution (16 page)

Chapter
7

An
Introduction to
Metabolism. Two goals. Two fuels

Metabolism – the conversion of food
to
energy and cell materials
– is as complicated as you would expect but it is possible to get an
idea of
the big picture. The approach here is the systems or "black box"
strategy –
getting some information just by looking at the inputs and outputs to a
system
even if we don't know the details of what's going on inside. As we find
the
details we can nest black boxes inside each other. It is a way of
organizing
limited information. The method is favored by engineers who are the
people most
unhappy with the idea that they don't know anything at all.

The black box of life.

You knew, before you started this,
what we do in metabolism:
we take in food and oxygen. We put out CO
₂
and
water. Somehow this
gives us the energy for life and provides the material to build body
components. Looking at the inputs and outputs, you don't have to know
too much
chemistry to figure out that inside the black box, living systems use
oxidation, like burning fuels for heat or to run a machine.

Technically speaking, this is an
oxidation-reduction
reaction (
redox
, for
short). Oxidation, in this
context, means combination with oxygen or loss of hydrogen atoms;
reduction
means loss of oxygen or gain of hydrogen; we say that the carbon atoms
in the
food get oxidized and the oxygen gets reduced (to water). Like the
common
oxidation reactions you know (combustion in a furnace or in an
automobile
engine), this produces energy which can be used to do work. Some work
is
mechanical work – moving muscles – but most of the energy is used for
chemical
work: making body material and keeping biological structures intact and
generally keeping things running.

Chemical energy.

Energy in physics is not too
different from common usage. It
means the ability to do work. Complicated as systems can get, basically
we are
talking about lifting a weight on a pulley. In chemistry, energy is
identified
with the progress of a reaction. If a chemical reaction goes by itself
(not
necessarily quickly) without addition of work, we know that, in the
end, we can
use it to lift a weight. If you have studied any chemistry, you
remember the
equilibrium constant which tells you how much product you have at the
end of
the reaction. If the constant is favorable, if you have a lot of
product, the
reaction is said to be exergonic, down-hill and spontaneous. You can
get energy
from it.

 Metabolism:
two goals.

Two major goals in human energy
metabolism: first, provide
energy for life processes and second, maintain more or less constant
levels of
blood glucose. Too little glucose is not good because it is a major
fuel but
too much is also not good because glucose is chemically reactive and
can take out
body proteins in side reactions as described in the previous chapter.

Energy
in biochemistry
is
described in terms of a particular chemical reaction. When you study
biochemistry, you get to examine what the compounds do precisely but
then you
do use them as the abbreviations. The simple chemical in the reaction
is
phosphoric acid.

Important
note:
in
biochemistry, the names of acids are interchangeable with the salt name
of the
acid – if you know a little chemistry, it is because at pH 7,
carboxylic acid or
phosphoric acid, are completely converted to the charged form
(phosphate). So:
pyruvic acid is the same as pyruvate; lactic acid is the same as
lactate;
phosphoric acid is the same as phosphate, etc.

Phosphate is abbreviated P
_i
.
The "i" stands for
"inorganic." It is a slightly archaic term but still used and P
_i
is
sometimes read as "inorganic phosphate." So, the big energy system in
biology
is:

ADP + P
_i
⇆
ATP
+ H
₂
O (1)

Energy storage in living systems is
taken as the synthesis
of ATP from ADP (the other reactants are assumed). Utilizing energy is
accompanied by the conversion of ATP back to the low energy form ADP.
The
reverse reaction in equation (1) is called hydrolysis (adding water) of
ATP.
The reaction is favored in the reverse direction. You need energy to
make ATP
from ADP. In metabolism, the "energy" in food is used to make ATP. The
energy
in the ATP is used to do chemical work, make proteins, cell material.
The ATP
is converted to ADP.

Textbooks frequently refer to ATP as
a "high energy
molecule" but it is not exactly the compound itself but rather the
reaction
(synthesis and hydrolysis) that is high energy. For the moment, we can
think of
ATP as the "coin of energy exchange in metabolism" and, roughly, the
ATP:ADP
ratio as the energy state of the system.

Metabolism:
two fuels

In fulfilling the two goals, two
kinds of fuels are used:
glucose itself and the
two carbon
compound,
acetyl-Coenzyme A.
(abbreviated
acetyl-CoA
or
acetyl-SCoA the S, meant to show that the compound contains sulfur, is
not
pronounced). Coenzyme A is a complicated molecule, but, like many such
molecules, like ATP and ADP, it is always referred to in this way so it
is not
important to know the detailed structure.). Definitions:

Coenzymes
are small molecules
that take part in the metabolic changes in living systems. They can be
involved
in energy metabolism (like ATP/ADP) or other reactions. The
oxidation-reduction
coenzymes are the NAD molecules (always abbreviated but stands for
nicotinamide
adenine dinucleotide if you are bothered by free-floating
abbreviations). Two
forms: oxidized, NAD
⁺
and reduced, NADH.

Most ATP in the cell comes from the
oxidation of acetyl-CoA
but glucose can be converted to acetyl-CoA. Acetyl-CoA also comes from
fat and,
to a smaller extent, from protein. Glucose, itself, can also be formed
from
protein but glucose
cannot
be formed from acetyl-CoA. The significance of the last statement is
that:
fat can be formed from
glucose but,
with a few minor
exceptions,
glucose cannot be formed from fat.
Historically, the
challenge for biochemistry was to explain how the energy
from an
oxidation-reduction reaction could be used to carry out the synthesis
of ATP
which has a different mechanism (phosphate transfer). The process is
called
oxidative phosphorylation and was only figured out about fifty years
ago and
was only worked out relatively recently..

Again, two goal: provide energy as
ATP and
maintain a pretty much
constant level of blood glucose for those cells that require it; the
brain, in
particular, can't use fat, that is, fatty acids, as a fuel.

Breaking into the black box,
oxidation of
food by oxygen is
separated into two different processes. The food never sees the oxygen
but
instead there is an intermediary player. The intermediate agent, the
redox
coenzyme, NAD
⁺
does the oxidation of food and
the NADH (the product,
the reduced form) is re-oxidized by molecular oxygen. Why do we do it
this way? In
general, biochemical reactions proceed in small steps to allow for
control and
for capturing energy. Even if we could do it all in one big
blast, like an
automobile engine – living tissues do not do well with explosive, high
temperature reactions – we would have little control over it and we
would not
be able to capture the energy in a usable chemical form. 

Glycolysis

Glucose is at the center of
metabolism.
Glycolysis, the
collection of early steps in its processing is common to almost all
organisms. Glycolysis
(sugar splitting) ultimately provides two molecules of the three-carbon
compound known as pyruvic acid (pyruvate). In most cells, the pyruvate
from
glycolysis is oxidized to acetyl-CoA which is the input for aerobic
(oxygen-based) metabolism and the main source of energy for most
mammalian
cells. One of the functions glycolysis is to provide acetyl-CoA. Some
cells,
however can run on glycolysis alone. Such cells are said to have a
glycolytic
metabolism and can convert pyruvate to a number of different compounds,
most
commonly lactic acid.

Glycolytic
metabolism

Many microorganisms are glycolytic.
Much
of our understanding of
glycolysis comes from the study of bacteria and the process of
fermentation.
The final product can be very different for different organisms.
Alcoholic
fermentation involves the conversion of pyruvate to a two carbon
compound
acetaldehyde which, in turn, is converted to ethanol. (When you ingest
alcohol
your liver runs this reaction backwards, converting alcohol to
acetaldehyde and
then to acetyl-CoA which is further oxidized. Other kinds of glycolytic
bacteria, like those in yoghurt, convert pyruvate to lactic acid
(lactate)
accounting for the acidity of yoghurt. Mammalian cells can also carry
out this
transformation. Brain, central nervous system, red blood cells and
rapidly
exercising muscle are the most common of the glycolytic tissues
producing
lactate. It used to be said that the lactate produced by exercising
muscle was
the cause of delayed-onset muscle soreness (sometimes written DOMS,
pronounced
as the letters) but this is not true. The cause of DOMS is not known
but the
lactic acid is metabolized, that is, provides fuel for other muscle
cells, and
is long gone by the time soreness sets in.

Oxidative metabolism

Acetyl-CoA is the main substrate for
the oxidative process
that produces CO
₂
released from the black box of
life. The process
is frequently called the Krebs cycle after Sir Hans Krebs who was the
major
researcher in assembling the observations on where particular carbon
atoms went
when different foods were fed to a tissue or organism, into a coherent
mechanism. Oxidation of such a small molecule by itself would have to
take
place in a small number of steps and would not allow the kind of
control that
it is necessary to keep a biological system responsive to different
conditions,
so the two carbons of actetyl-CoA are attached to a carrier to form a
6-carbon
molecule, called citric acid, or citrate. For this reason the cycle is
also
frequently referred to as the citric acid cycle. In the way of knowing
the
names, citric acid is a tricarboxylic acid, or TCA for short, so the
process is
also referred to as the TCA cycle. All three names are used. Krebs
called it
the TCA cycle and we will use that most of the time.

Where does the energy
come from?

The TCA cycle is complicated but a
rough description is that
the substrate, acetyl-CoA is bound to a carrier to form an compound,
citric
acid, that is oxidized step-wise, primarily by the redox coenzyme NAD
⁺
.
The product of the reaction is CO
₂
and the
reduced form of the
coenzyme, NADH. NADH is the ultimate reducing agent (transfers H) that
turns
oxygen to water as in the black box picture. This process, the electron
transport chain is, as the name tells you, a sequence of reactions
that, in
effect, transfer electrons. The net effect is the reduction of
molecular oxygen
to water. Somehow this converts ADP to ATP. This is the mechanism for
capturing
the energy of burning food in the potential to convert ATP back to ADP,
that
is, stores chemical energy. The process still mysterious when I was in
graduate
school, is now understood. The idea behind it, the Chemiosmotic Theory
– really
no longer a theory – is due largely to a single man, Peter Mitchell.
The
overall process would be a major digression from where we are now, so
Chemiosmotic
and
Peter
Mitchell
are the
things to Google. Because it involves oxygen, obtaining energy from The
TCA
cycle-electron transport chain is referred to as oxidative metabolism,
distinct
from glycolytic metabolism which may precede it. Glycolysis provides
acetyl-CoA
for the TCA cycle.