Msb 206. amino acid catab and fates of cs.2014

Amino acid catabolism
Amino acid degradation
Fates of carbon skeleton
GKM/MUSOM/MSB206:.REP.URI.SYS.2014
MSB 206: REPRODUCTIVE
AND URINARY SYSTEM
08/03/14

Amino acids and their R groups
• Twenty different amino acid are found in proteins
• Most microorganisms and plants can
biosynthesize all 20
• Animals (including humans) must obtain some of
the amino acids from the diet.
• The amino acids that an organism cannot
synthesize on its own are referred to as essential
amino acids.
• Humans require 8 essential amino acids
08/03/14

Propertiesofaminoacids
GKM/MUSOM/MSB206:.REP.URI.SYS.201408/03/14

Oxidative degradation of amino acids
• Under three different metabolic circumstances
in animals:
1. During the normal synthesis and degradation of
cellular protein;
 some amino acids that are released from protein breakdown
and are not needed for new protein synthesis undergo
oxidative degradation.
2. When a diet is rich in protein and the ingested;
amino acids exceed the body’s needs for protein synthesis, the
surplus is catabolized; amino acids cannot be stored.
3. During starvation or in uncontrolled diabetes
mellitus;
when carbohydrates are either unavailable or not properly
utilized, cellular proteins are used as fuel.

Removal of the alpha amino group
• Every amino acid contains an
amino group
• The pathways for amino acid
degradation therefore include a
key 1ST
step in which the amino
group is separated from the carbon
skeleton
• It is then shunted into the
pathways of amino group
metabolism – different based on
different organism.

There are multiple transaminase enzymes which vary in
substrate specificity.
Some show preference for particular amino acids or classes of
amino acids as amino group donors, and/or for particular α-
keto acid acceptors.
H
R1 C COO
-
+ R2 C COO
-
NH3
+
O
Transaminase
H
R1 C COO
-
+ R2 C COO
-
O NH3
+
Role of Transaminases (aminotransferases)
Catalyze the reversible reaction
aa
aaka
ka
08/03/14

Example of a Transaminase reaction:
 Aspartate donates its amino group, becoming
the α-keto acid oxaloacetate.
 α-Ketoglutarate accepts the amino group,
becoming the amino acid glutamate.
aspartate α-ketoglutarate oxaloacetate glutamate
Aminotransferase (Transaminase)
COO−
CH2
CH2
C
COO−
O
COO−
CH2
HC
COO−
NH3
+
COO−
CH2
CH2
HC
COO−
NH3
+
COO−
CH2
C
COO−
O+ +

In another example, alanine becomes pyruvate as
the amino group is transferred to α-ketoglutarate.
alanine α-ketoglutarate pyruvate glutamate
COO−
CH2
CH2
C
COO−
O
CH3
HC
COO−
NH3
+
COO−
CH2
CH2
HC
COO−
NH3
+
CH3
C
COO−
O+ +

The Ammonia that is generated
following deamination rxn is
Transported in the Bloodstream
Safely as Glutamate or in
combination with Glutamate to
form Glutamine
• Un-needed glutamine is
processed in intestines
the, kidneys and liver

Pyruvate – Alanine in SM
• In skeletal muscle, excess amino groups are
generally transferred to pyruvate to form
alanine
• Other than Gln and Glu, Alanine is therefore
another important molecule in the transport
of amino groups to the liver.
– See next slide

Glutamate can Donate
Ammonia to Pyruvate to
Make Alanine
• Vigorously working muscles
operate nearly anaerobically and
rely on glycolysis for energy
• Glycolysis yields pyruvate that
muscles cannot metabolize
aerobically; if not eliminated lactic
acid will build up
• This pyruvate can be converted
to alanine for transport of NH4
into liver

Aminotransferases and pyridoxal phosphate
• Aminotransferases are classic examples of enzymes
catalyzing bimolecular Ping-Pong reactions
• In these rxns, the first substrate reacts and the product
must leave the active site before the second substrate
can bind.
• The incoming amino acid thus binds to the active site,
donates its amino group to pyridoxal phosphate, and
departs in the form of an –keto acid.
• The incoming -keto acid then binds, accepts the amino
group from pyridoxamine phosphate, and departs in the
form of an amino acid.

The prosthetic group of Transaminase is
pyridoxal phosphate (PLP), a derivative of
vitamin B6
.
pyridoxal phosphate (PLP)
N
H
C
O
P
O−
O
O
OH
CH3
C
H O
−
+
H2

In the resting state, the aldehyde group of pyridoxal
phosphate is in a Schiff base linkage to the ε-amino
group of an enzyme lysine side-chain.
N
H
C
O
P
O−
O
O
O−
CH3
HC
−
+
H2
N
(CH2)4
Enz
H
+
R
H
C COO−
NH2
Enzyme (Lys)-PLP Schiff base
Amino acid

The active site lysine extracts H+
, promoting
tautomerization, followed by reprotonation &
hydrolysis.
N
H
C
O
P
O−
O
O
O−
CH3
HC
−
+
H2
N
H
C
H
+
R COO−
Enz−Lys−NH2
Amino acid-PLP Shiff base (aldimine)
The α-amino group
of a substrate amino
acid displaces the
enzyme lysine, to
form a Schiff base
linkage to PLP.

The amino group remains on what is now pyridoxamine
phosphate (PMP).
A different α-keto acid reacts with PMP and the process
reverses, to complete the reaction.
N
H
C
O
P
O−
O
O
OH
CH3
CH2
NH2
H2
R C COO−
O
−
+
Enz−Lys−NH2
Pyridoxamine phosphate (PMP)
α-keto acidWhat was an
amino acid
leaves as an
α-keto acid.

Several other enzymes that catalyze metabolism or
synthesis of amino acids also utilize PLP as prosthetic
group, and have mechanisms involving a Schiff base
linkage of the amino group to PLP.
N
H
C
O
P
O−
O
O
O−
CH3
HC
−
+
H2
N
H
C
H
+
R COO−
Enz−Lys−NH2
Amino acid-PLP Shiff base (aldimine)

Amino acid Carbon skeleton
• Amino acids lose their amino groups to form -keto
acids - the “carbon skeletons” of amino acids.
• The -keto acids undergo oxidation to CO2 and H2O or
can be converted by gluconeogenesis into glucose,
the fuel for brain.
• As in carbohydrate and fatty acid catabolism, the
processes of amino acid degradation converge on
the central catabolic pathways.
• The carbon skeletons of most amino acids find their
way to the citric acid cycle.

central catabolic pathways
• In cytoplasm (1)
• In mitochondria (2, 3 & 4)
25-19
Others e.g;
Gluconeogenesis
Glycogenesis

Amino Acid Carbon Skeletons
Amino acids are grouped into 2 classes, based on
whether or not their carbon skeletons can be
converted to glucose:
 glucogenic
 ketogenic.

Carbon skeletons of glucogenic amino acids are
degraded to:
 pyruvate, or
 a 4-C or 5-C intermediate of Krebs Cycle. These
are precursors for gluconeogenesis.
Glucogenic amino acids are the major carbon source
for gluconeogenesis when glucose levels are low.
They can also be catabolized for energy, or converted
to glycogen or fatty acids for energy storage.

Summary of
Amino Acid
Catabolism

Gluconeogenesis:
synthesis
of Glucose from none
carbohydrates
Gluconeogenesis is not just
glycolysis in reverse--the
enzymes in green print
catalyze irreversible reactions

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.
For every 2-C acetyl residue entering Krebs Cycle, 2C
leave as CO2
.
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.
08/03/14

The 3-C α-keto acid pyruvate is produced from alanine,
cysteine, glycine, serine, & threonine.
Alanine deamination via Transaminase directly yields
pyruvate.
alanine α-ketoglutarate pyruvate glutamate
COO−
CH2
CH2
C
COO−
O
CH3
HC
COO−
NH3
+
COO−
CH2
CH2
HC
COO−
NH3
+
CH3
C
COO−
O+ +

Serine is deaminated to pyruvate via Serine Dehydratase.
Glycine, which is also product of threonine catabolism, is
converted to serine by a reaction involving
tetrahydrofolate (to be discussed later).
HO CH2
H
C COO−
NH3
+
C COO−
OH2O NH4
+
C COO−
NH3
+
H2C H3C
H2O
serine aminoacrylate pyruvate
Serine Dehydratase
08/03/14

The 4-C Krebs Cycle intermediate oxaloacetate is produced from
aspartate & asparagine.
Aspartate transamination yields oxaloacetate.
Aspartate is also converted to fumarate in Urea Cycle. Fumarate
is converted to oxaloacetate in Krebs cycle.
COO−
CH2
CH2
C
COO−
O
COO−
CH2
HC
COO−
NH3
+
COO−
CH2
CH2
HC
COO−
NH3
+
COO−
CH2
C
COO−
O+ +

Asparagine loses the amino group from its R-group
by hydrolysis catalyzed by Asparaginase.
This yields aspartate, which can be converted to
oxaloacetate, e.g., by transamination.
C
CH2
HC
COO−
NH3
+
OH2N
COO−
CH2
HC
COO−
NH3
+
H2O NH4
+
asparagine aspartate
Asparaginase

The 4-C Krebs Cycle intermediate succinyl-
CoA is produced from isoleucine, threonine,
valine, & methionine.
Propionyl-CoA, an intermediate on these
pathways, is also a product of β-oxidation of
fatty acids with an odd number of C atoms.
NB: Isoleucine and Valine are branched-chain
amino acids
08/03/14

The branched chain amino acids initially share a
common pathway.
Branched Chain α-Keto Acid Dehydrogenase
(BCKDH) is a multi-subunit complex.
Genetic deficiency of BCKDH is called Maple Syrup
Urine Disease (MSUD).
High concentrations of branched chain keto acids in
urine give it a characteristic odor.

MSUD
• People with MSUD have a mutation that
results in a deficiency for one of the 6 proteins
that make up this complex.
• Therefore, they can't break down leucine,
isoleucine, and valine.
• They end up with dangerously high levels of
these amino acids in their blood, causing the
rapid degeneration of brain cells and death if
left untreated.

Propionyl-CoA is carboxylated to methylmalonyl-CoA.
A racemase yields the L-isomer essential to the subsequent
reaction.
Methylmalonyl-CoA Mutase catalyzes a molecular
rearrangement: the branched C chain of methylmalonyl-CoA is
converted to the linear C chain of succinyl-CoA.
C CH3
C S-CoA
O
C CH3
C S-CoA
O
COO−
C
C S-CoA
O
COO−
C C
COO−
C
C
O
H
H
CoA-S H
HH HH
H
H
H
H
HCO3
−
ATP ADP
+ Pi
propionyl-CoA D-methylmalonyl-CoA L-methylmalonyl-CoA succinyl-CoA
Propionyl-CoA Methylmalonyl-CoA Methylmalonyl-CoA
Carboxylase (Biotin) Racemase Mutase (B12)
bk

The 5-C Krebs Cycle intermediate α-ketoglutarate is
produced from arginine, glutamate, glutamine,
histidine, & proline.
Glutamate deamination via Transaminase directly yields
α-ketoglutarate.
COO−
CH2
CH2
C
COO−
O
COO−
CH2
HC
COO−
NH3
+
COO−
CH2
CH2
HC
COO−
NH3
+
COO−
CH2
C
COO−
O+ +

Glutamate deamination by Glutamate Dehydrogenase
also directly yields α-ketoglutarate.
−
OOC
H2
C
H2
C C COO−
O
+ NH4
+
NAD(P)+
NAD(P)H
−
OOC
H2
C
H2
C C COO−
NH3
+
H
glutamate
α-ketoglutarate
Glutamate Dehydrogenase

Histidine is first converted to glutamate. The last step in this
pathway involves the cofactor tetrahydrofolate.
Tetrahydrofolate (THF), which has a pteridine ring, is a reduced
form of the B vitamin folate.
N
H
H
NN
HN
H2N H
H
H
CH2
HNO C
O
N
H
C
H
COO−
C
H2
C
H2
COO−
Tetrahydrofolate (THF)
pteridine ρ-aminobenzoate glutamate

In the pathway of
histidine degradation,
N-
formiminoglutamate is
converted to glutamate
by transfer of the
formimino group to
THF, yielding N5
-
formimino-THF.
HC C CH2
H
C COO−
NH3
+N NH
C
H
−
OOC
H
C CH2 CH2 COO−
HN NH
C
H
−
OOC
H
C CH2 CH2 COO−
NH3
+
THF
N 5
-formimino-THF
NH4
+
H2O
H2O
histidine
N-formimino-
glutamate
glutamateGKM/MUSOM/MSB206:.REP.URI.SYS.2014
08/03/14

Aromatic Amino Acids
Aromatic amino acids phenylalanine &
tyrosine are catabolized to fumarate and
acetoacetate.
Hydroxylation of phenylalanine to form
tyrosine involves the reductant
tetrahydrobiopterin.
Biopterin, like folate, has a pteridine ring.
08/03/14

Overall the reaction is considered a mixed function
oxidation, because one O atom of O2 is reduced to water
while the other is incorporated into the amino acid
product.
CH2 CH COO−
NH3
+
CH2 CH COO−
NH3
+
HO
phenylalanine
tyrosine
O2 + tetrahydrobiopterin
H2O + dihydrobiopterin
Phenylalanine
Hydroxylase
08/03/14

deamination via transaminase) accumulate in blood & urine.
Mental retardation results unless treatment begins immediately after
birth. Treatment consists of limiting phenylalanine intake to levels barely
adequate to support growth. Tyrosine, an essential nutrient for
individuals with phenylketonuria, must be supplied in the diet.
Transaminase
Phenylalanine Phenylpyruvate
(Phenylketone)
Phenylalanine Deficient in
Hydroxylase Phenylketonuria
Tyrosine Melanins
Multiple
Reactions
Fumarate + Acetoacetate
Genetic deficiency of
Phenylalanine Hydroxylase
leads to the disease
phenylketonuria.
Phenylalanine &
phenylpyruvate (the product
of phenylalanine

High [phenylalanine]
inhibits
Tyrosine Hydroxylase,
on the pathway for
synthesis of the pigment
melanin from tyrosine.
Transaminase
Phenylalanine Phenylpyruvate
(Phenylketone)
Phenylalanine Deficient in
Hydroxylase Phenylketonuria
Tyrosine Melanins
Multiple
Reactions
Fumarate + Acetoacetate
Tyrosine is a precursor for synthesis of melanins
and of epinephrine and norepinephrine.
Individuals with phenylketonuria have light skin &
hair color.
08/03/14

H3C S
H2
C
H2
C
H
C COO−
NH3+CH2
+
O
OHOH
HH
HH
Adenine
H3C S
H2
C
H2
C
H
C COO−
NH3+
HS
H2
C
H2
C
H
C COO−
NH3+
S
H2
C
H2
C
H
C COO−
NH3+CH2
O
OHOH
HH
HH
Adenine
methionine
homocysteine
S-adenosyl-
methionine
(SAM)
S-adenosyl-
homocysteine
ATP PPi + Pi
adenosine H2O
acceptor
methylated acceptor
THF
N5
-methyl-THF
Methionine → S-Adenosylmethionine by ATP-dependent reaction.

H3C S C
H2
C
H2
H
C COO−
NH3+CH2
+
O
OHOH
HH
HH
Adenine
HS C
H2
C
H2
H
C COO−
NH3+
S C
H2
C
H2
H
C COO−
NH3+CH2
O
OHOH
HH
HH
Adenine
homocysteine
S-adenosyl-
methionine
(SAM)
S-adenosyl-
homocysteine
adenosine H2O
Acceptor (THF)
methylated acceptor)
SAM is a methyl group donor in
synthetic reactions.
The resulting
S-adenosylhomocysteine is
hydrolyzed to homocysteine.
Homocysteine may be
catabolized via a complex
pathway to cysteine & succinyl-
CoA.
08/03/14

Or methionine may be
regenerated from homocysteine
by methyl transfer from
N5
-methyl-tetrahydrofolate, via a
methyltransferase enzyme that
uses B12 as prosthetic group.
The methyl group is transferred
from THF to B12 to homocysteine.
Another pathway converts
homocysteine to glutathione.
H3C S C
H2
C
H2
H
C COO−
NH3+
HS C
H2
C
H2
H
C COO−
NH3+
methionine
homocysteine
THF
N5
-methyl-THF

The Catabolism of Lysine and Tryptophan are quite
complex and will not be discussed in detail

08/03/14

The End
Thanks for your attention

Msb 206. amino acid catab and fates of cs.2014

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