α-Ketoglutaric acid is one of two ketone derivatives of glutaric acid.
Its anion, α-ketoglutarate is an important biological compound. It is the
keto acid produced by deamination of glutamate, and is an intermediate in the
Krebs cycle. Functions
= Krebs cycle = α-Ketoglutarate is a key intermediate in
the Krebs cycle, coming after isocitrate and before succinyl CoA. Anaplerotic
reactions can replenish the cycle at this juncture by synthesizing
α-ketoglutarate from transamination of glutamate, or through action of
glutamate dehydrogenase on glutamate. = Formation of amino acids =
Glutamine is synthesized from glutamate by glutamine synthetase, which utilizes
an ATP to form glutamyl phosphate; this intermediate is attacked by ammonia as a
nucleophile giving glutamine and inorganic phosphate.
= Nitrogen transporter = Another function is to combine with
nitrogen released in the cell, therefore preventing nitrogen overload.
α-Ketoglutarate is one of the most important nitrogen transporters in
metabolic pathways. The amino groups of amino acids are attached to it and
carried to the liver where the urea cycle takes place.
α-Ketoglutarate is transaminated, along with glutamine, to form the excitatory
neurotransmitter glutamate. Glutamate can then be decarboxylated into the
inhibitory neurotransmitter GABA. It is reported that high ammonia and/or
high nitrogen levels may occur with high protein intake, excessive aluminum
exposure, Reye's syndrome, cirrhosis, and urea cycle disorder.
It plays a role in detoxification of ammonia in brain.
= Relationship to molecular oxygen = Acting as a co-substrate, it also plays
important function in oxidation reactions involving molecular oxygen.
Molecular oxygen directly oxidizes many compounds to produce useful products in
an organism, such as antibiotics, etc., in reactions catalyzed by oxygenases. In
many oxygenases, α-ketoglutarate helps the reaction by being oxidized together
with the main substrate. In fact, one of the α-ketoglutarate-dependent oxygenases
is an O2 sensor, informing the organism the oxygen level in its environment.
In combination with molecular oxygen, alpha-ketoglutarate is one of the
requirements for the hydroxylation of proline to hydroxyproline in the
production of Type 1 Collagen. = Antioxidant =
α-Ketoglutarate, which is known to be released by several cell types,
decreased the levels of hydrogen peroxide, and the α-ketoglutarate was
depleted and converted to succinate in cell culture media.
= Longevity = A study released on May 14, 2014 links
α-ketoglutarate with significantly increased lifespan in nematode worms.
= Immune Regulation = A recent study has shown that
α-ketoglutarate promotes TH1 differentiation and depletion of
Glutamine (by depleting its metabolite α-ketoglutarate favors Treg
differentiation. It might play a role in skewing the balance in favor of Tregs in
the setting of amino acid deprivation that can be seen in the tumor
microenvironment. Production
α-Ketoglutarate can be produced by: Oxidative decarboxylation of isocitrate
by isocitrate dehydrogenase; Oxidative deamination of glutamate by
glutamate dehydrogenase. Alpha-ketoglutarate can be used to
produce: Creatine-alpha ketoglutarate
Interactive pathway map Click on genes, proteins and metabolites
below to link to respective articles. References