Download Four Amino Acids Are Converted to Succinyl

Four Amino Acids Are Converted to SuccinylCoA
• The carbon skeletons of methionine, isoleucine, threonine,and
valine are degraded by pathways that yield succinyl-CoA, an
intermediate of the citric acid cycle.
• Only portions of the carbon skeletons are converted to succinylCoA.
• Four-fifths of the carbons of valine, three-fifths of those of
methionine, and half of those of isoleucine form suuccinyl-CoA.
• The carboxyl carbons of of all three form CO2.
• The terminal two carbons of isoleucine form acetyl-CoA.
• The methyl group of methionine is removed.
• Methionine donates its methyl group to one of several possible
acceptors through S-adenosylmethionine, and three of its four
remaining carbon atoms are converted to the propionate of
propionyl-CoA, a precursor of succinyl-CoA.
Methionine, isoleucine and valine are converted
to succinyl CoA
• The 4-C Krebs Cycle intermediate succinyl-CoA is
produced from isoleucine, valine, & methionine.
• All essential.
• Propionyl-CoA, an intermediate on these pathways, is
also a product of β-oxidation of fatty acids with an odd
number of C atoms.
• Methionin could be
metabolised to cystein
Methionine
• Methionine Degradation Requires
the Formation of a Key Methyl
Donor, S Adenosylmethionine.
• IN The first step, L-Methionine
condenses with ATP forming Sadenosylmethionine (SAM),
active methionine, a common
and important methyl donor in
the cell.
• The activated S-methyl group
may transfer to various acceptors.
• Removal of methyl group from Sadenosyl homocystein.
• Hydrolysis of the S-C bond yields
L-homocystein and adenosine.
• Homocysteine may be catabolized
to cysteine & succinyl-CoA.
• Or methionine may be
regenerated from homocysteine
Methionine
H3C
H3C
S
H2
C
H2
C
H
C
COO−
S
H2
C
+
H2
C
H
C
CH2
COO−
N H 3+
Ade ni n e
N H 3+
m ethionin e
O
ATP PPi + Pi
H
H
OH
H
OH
H
acceptor
THF
N 5 -m ethyl-T H F
m ethylated acceptor
ad enosine H 2 O
HS
H2
C
S -ad en osylm ethionin e
(S A M )
H2
C
H
C
COO−
H2
C
S
H2
C
H
C
CH2
COO−
N H 3+
Ade ni n e
h om ocystein e
O
N H 3+
H
H
OH
H
OH
H
S -a den osylh om ocystein e
• Methionine → S-Adenosylmethionine by ATP-dependent reaction.
• methionine may be regenerated from homocysteine by methyl transfer from N5-methyltetrahydrofolate, via a methyltransferase enzyme that uses B12 as prosthetic group.
• The methyl group is transferred from THF to B12 to homocysteine.
Homocysteine
• Homocysteine has two fates.
• If there is a deficiency of methionine, homocysteine may be
remethylated to methionine. If methionine stores are adequate,
homocysteine may enter the transsulfuration pathway, where it is
converted to cysteine.
• Homocysteine condenses with serine, forming cystathionine, which
is hydrolyzed to α-ketobutyrate and cysteine.
• This vitamin B6–requiring sequence has the net effect of converting
serine to cysteine, and homocysteine to α-ketobutyrate.
• α-ketobutyrate is oxidatively decarboxylated to form propionyl CoA
by The enzyme α-ketoacid dehydrogenase complex.
• Propionyl CoA is processed to succinyl CoA.
• Elevations in plasma homocysteine levels promote oxidative
damage, inflammation, and endothelial dysfunction, and are an
independent risk factor for occlusive vascular disease.
Resynthesis of methionine
•
•
Homocysteine accepts a
methyl group from N5methyltetrahydrofolate
(N5-methyl-THF) in a
reaction requiring
methylcobalamin, a
coenzyme derived from
vitamin Bl2.
The methyl group is
transferred from the B12
derivative to
homocysteine, and
cobalamin is recharged
from N5-methyl-THF.
Met, Ile, Thr, Val
catabolism
• Isoleucine :undergoes transamination, followed by
oxidative decarboxylation of the resulting - keto acid.
• The remaining five-carbon skeleton is further oxidized
to acetyl-CoA(2 carbon) and propionyl-CoA (3 carbon).
• Valine: undergoes transamination and decarboxylation,
then a series of oxidation reactions that convert the
remaining four carbons to propionyl-CoA.
• Threonine: is also converted in two steps to propionylCoA. (This is the primary pathway for threonine
degradation in humans)
Oxidation of propionyl-CoA to
Succinyl CoA
• The propionyl-CoA derived
from these three amino acids
is converted to succinyl-CoA by
carboxylation to
D- methylmalonyl- CoA,
epimerization to the
L-methylmalonyl-CoA, and
conversion to succinyl-CoA by
the coenzyme B12–dependent
methylmalonyl-CoA mutase
reaction.
• In the rare genetic disease
known as methylmalonic
acidemia, methylmalonyl-CoA
mutase is lacking with serious
metabolic consequences.
• Carbon skeletons of ketogenic amino acids are
degraded to:
acetyl-CoA, or
acetoacetate.
• Acetyl CoA, & its precursor acetoacetate, cannot
yield net production of oxaloacetate, the
gluconeogenesis precursor.
• Carbon skeletons of ketogenic amino acids can be
catabolized for energy in Krebs Cycle, or converted to
ketone bodies or fatty acids.
• They cannot be converted to glucose.
Amino acids that form acetyl CoA or
acetoacetyl CoA
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Seven amino acids form acetyl CoA and/or acetoacetyl-CoA.
These amino acids are lysine, leucine,tryptophan, phenylalanine,
tyrosine,, isoleucine, and threonine.
Leucine is ketogenic, forming acetyl CoA and acetoacetate.
Lysine is exclusively ketogenic amino acid, converted to
acetoacetyl CoA.
Tryptophan is both glucogenic and ketogenic because its
metabolism yields alanine and acetoacetyl CoA.
Isoleucine is both ketogenic and glucogenic, because its
metabolism yields acetyl CoA and propionyl CoA.
Leucine, isoleucine, lysine, and tryptophan form acetyl CoA or
acetoacetyl.
Phenylalanine and tyrosine give to acetoacetate during their
catabolism.
Threonine yields some acetyl-CoA via minor pathway.
Leucine, lysine, phenylalanine, tyrosine and tryptophan yield
acetyl-CoA via acetoacetyl-CoA.
Isoleucine, leucine, threonine, and tryptophan also form acetylCoA directly.
Catabolic pathways for tryptophan, lysine,
phenylalanine,tyrosine, leucine, and isoleucine
• some of their
carbons (red) to
acetyl-CoA.
• Tryptophan, phenylalanine,tyrosine, and isoleucine also contribute carbons (blue) to
pyruvate or citric acid cycle intermediates.
Tryptophan
• Tryptophan breakdownis the most complex of all the
pathways of amino acid catabolism in animal tissues;
portions of tryptophan(four of its carbons) yield acetylCoA via acetoacetyl-CoA.
• Some of the intermediates in tryptophan catabolism
are precursors for the synthesis of other biomolecules
including nicotinate, a precursor of NAD and NADP in
animals; serotonin, a neurotransmitter in
vertebrates; and indoleacetate, a growth factor in
plants.
Phenylalanine
• Phenylalanine is hydroxylated to tyrosine.
• Phenylalanine and tyrosine have nine carbons .
They are degraded into two fragments, both of
which can enter the citric acid cycle: four of the
nine carbon atoms yield free acetoacetate, which
is converted to acetoacetyl-CoA and thus acetylCoA, and a second four-carbon fragment is
recovered as fumarate.
• Thus eight of the nine carbons of these two
amino acids thus enter the citric acid cycle; the
remaining carbon is lost as CO2.
Phenylalanine → Tyrosine
• Phenylalanine is hydroxylated to tyrosine by phenylalanine
hydroxylase.
• Phenylalanine hydroxylase (also called phenylalanine-4monooxygenase) is one of a general class of enzymes called
mixed-function oxidases, all of which catalyze
simultaneous hydroxylation of a substrate by an oxygen
atom of O2 and reduction of the other oxygen atom to
H2O.
• Phenylalanine hydroxylase requires the cofactor
tetrahydrobiopterin, which carries electrons from NADH to
O2 and becomes oxidized to dihydrobiopterin.
• It is subsequently reduced by the enzyme dihydrobiopterin
reductase in a reaction that requires NADH.
Role of tetrahydrobiopterine in phenylalanine
hydroxylase reaction
Tyrosine
• Transamination of tyrosine to p-hydroxyphenylpyruvate is catalyzed
by tyrosine α-ketoglutarate transaminase (tyrosine
aminotransferase).
• P-hydroxyphenylpyruvate forms homogentisate catalysed by phydroxyphenylpyruvate dioxygenase where ascorbic acid is the
reductant.
• Homogentisate oxidase opens the aromatic ring to form
maleylacetoacetate.
• Isomerization of maleylacetoacetate-cis, trans isomerase resulting
in the formation of fumarylacetoacetate.
• Hydrolysis of fumarylacetoacetate forms fumarate and
acetoacetate catalysed by fumarylacetoacetate hydrolase.
• The acetoacetate forms acetyl CoA plus acetate catalyzed by βketothiolase.
Phenylalanine and
Tyrosine
Metabolism