Introduction ATP. The Electrons from NAD travel through

Introduction inc                a
brief description of the citric acid cycle CHANGE

The Citric acid cycle (also known as the Krebs cycle and tricarboxylic
acid cycle/ TCA) is well defined, having been first described over 70 years ago
(H.A.Krebs, 1937). It has since been shown to be a crucial metabolic cycle:
both as an important step in the generation of ATP, and as an anabolic pathway;
producing many important compounds such as cholesterol (and consequently is
required for the synthesis of steroid hormones, for example), fatty acids and bases
(Donald 2006, p. 547, 556).

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The cycle can be seen in figure 1: 2 carbon molecules are
lost through each cycle as carbon dioxide, which are replenished using the
‘fuel’ for the cycle: acetyl Co-A. It reacts with the four-carbon compound
oxaloacetate to produce the six-carbon compound citrate, restarting the cycle. In
addition to carbon dioxide, water can be considered a waste product of the
cycle, however, as can be seen in the diagram, there is net use of water,
rather than release. The more beneficial products of the cycle are elections
(to reduce NAD+ and FADH+) and protons for the election
transport chain and chemiosmosis, for the production of ATP, as well as GTP which
can produce one molecule of ATP. Each cycle produces 3 molecules of NADH, 1 FADH2
and 1 GTP, as well as 2 molecules of Co2.

Oxidative phosphorylation 

Before considering the catabolic processes undergone in the TCA
cycle, it is important to consider oxidative phosphorylation. Since the TCA is
the final common pathway for the oxidation of carbohydrate, protein and lipids
(M.Akram, 2014), the NADH, FADH2 and protons produced from their
anabolism and entry into the TCA cycle are utilised in this final stage of
aerobic respiration.

The electrons from the reduced NAD and FAD molecules are
oxidised and travel down a transport chain, which in eukaryotes consists of
four complexes in the mitochondria’s inner membrane, before terminating at an
oxygen atom, combining with two protons to form the waste product water (Stryer
2015 p524-559) and there is a fifth complex: ATP synthase, that phosphorylates
ADP to ATP. The Electrons from NAD travel through complexes 1, 3 and 4, and the
electrons from FAD travel through complexes 2,3 and 4. The electrons are
transferred through the chain through redox reactions, which produce energy for
ATP synthase to function. The energy from the chain is used to actively
transport H+ ions across the mitochondria’s inner matrix. The pH and
electrical gradient that is produced from this is then utilised when the H+
ions travel back into the cell, down this gradient, through ATP synthase.
This energy is used to produce ATP.


Catabolic pathways

As mentioned, the TCA is the final common pathway for final
common pathway for the oxidation of carbohydrate, protein and lipids, each of
which shall be discussed in turn. Firstly, carbohydrates begin oxidation
through glycolysis. Since this essay is focused on the TCA cycle, only
glycolysis in aerobic conditions shall be considered. Glycolysis is a series of
ten chemical reactions in the cell cytosol that convert one glucose molecule to
two molecules of pyruvate (G. M. Bodner 1986), in addition, two molecules of
NAD+ are reduced, two molecules of ATP are formed and two molecules
of waste product, water are also produced. Pyruvate is then converted to 2
carbon acetyl Co-A in the ‘link reaction’, with carbon dioxide being produced
as a waste product. Since each glucose molecule produces two molecules of
acetyl co- A, the link reaction occurs twice per molecule of glucose.

Secondly, oxidised proteins can enter the TCA cycle through
3 different routes. Once they are deanimated, they can be converted to: an
intermediate constituent of the cycle, acetyl Co-A, or pyruvate (which can be
converted to either acetyl Co- A through the link reaction, or to oxaloacetate)
conversion to an intermediate (including oxaloacetate) is known as an Anaplerotic
reaction (O. E. Owen, 2002).


These entry points can be seen in figure 2; the ketogenic
acids: isoleucine, leucine, lysine, phenylalanine, tryptophan and tyrosine are
converted into acetyl Co-A, either directly, or through acetoacetyl CoA, as
Acetyl Co-A is the precursor to ketone bodies. Leucine and lysine are the only
‘pure’ ketogenic acids, as the others are also glucogenic, along with all other
amino acids, which is to say that they can undergo gluconeogenesis and be
converted into glucose.



Finally, when lipids are oxidised, they are first hydrolysed
into fatty acids and glycerol. Beta oxidation of fatty acids then either
converts them to acetyl Co-A if they have an even number of methylene bridges,
or they are converted to succinyl co-A if they have an odd number (E.P. Kennedy
1949), which enter the TCA cycle as an intermediate (K. Bartlett 2004).

Anabolic pathways

The opposite of antapleurosis is cataplerosis. If carbon
chains were added to the cycle, but not able to be removed from it, then it
would form a carbon sink, instead, it is able to be used as a reservoir, until
they are needed. IF ROOM, MENTION MALATE
SHUFFLE, ACETYL CO-A NEEDED FOR CHOLESTEROL. These cataplerotic products of
the TCA cycle can be seen in figure 3. They are wide ranging, from important
constituents of erythrocytes, such as haem, to bases, the backbone of DNA.


Firstly, some amino acids can be obtained from the cycle: Aspartate
transaminase catalyses the conversion of ?-ketoglutarate to glutamate, and
oxaloacetate to apartate through transamination. The amino group of ?-ketoglutarate
is transferred to aspartate and vice versa, so obtaining glutamate decreases
the levels of aspartate, and increasing aspartate levels uses glutamate.
Aspartate can then be converted into asparagine, methionine, lysine and
threonine, and threonine can be converted into isoleucine, whereas glutamate
can be converted into glutamine, proline and argenine.     SOURCE?

Citrate is required to transport acetyl Co-A formed from the
link reaction, a major component required for fatty acid and steroid synthesis
from the mitochondria to the cytosol (P.A.Srere 1953), since acetyl Co-A formed
from the link reaction after glycolysis is unable to leave the mitochondria. Citrate
leaves the mitochondria, and ATP citrate lyase breaks it back into acetyl Co-A
and oxaloacetate. Acetyl Co-A can then either be converted into malonyl Co-A by acetyl Co-A carboxylase to
become a fatty acid (P.Ferré 2007), or to HMG Co-A in a condensation reaction
with a acetoacetyl-CoA.

Succinyl Co-A is an important component in the pathway to
produce porphyrins, such as haem (R. E. Labbe 1965) the oxygen carrying
component of haemoglobin in erythrocytes. It is combined with glycine by 5-Aminolevulinate
synthase to form ?-aminolevulinic acid, a haeme precursor (G.A. Hunter 2011)


Finally, gluconeogenesis can occur from the TCA cycle. Since
the decarboxylation of pyruvate to form acetyl Co-A is irreversible,
oxaloacetate is required for gluconeogenesis. It leaves the mitochondrion
through the malate shuffle, which can be seen in figure 3. Since oxaloacetate cannot
leave mitochondria itself, malate is transported out into the cytosol, and
oxidised using NADH. Oxaloacetate then undergoes a series of steps in the
cytosol to become free glucose (R.Marco 1974) NAME IF ROOM




Regulation of the TCA cycle, for example under different
nutritional (e.g. starved, fed, during exercise) conditions CHANGE