Amino acid metabolism - JSMU Lecture... · Transamination In transamination • Amino acids are...
Transcript of Amino acid metabolism - JSMU Lecture... · Transamination In transamination • Amino acids are...
Amino acid metabolism
The important reaction commonly employed in the breakdown
of an amino acid is always the removal of its -amino group.
The product ammonia is excreted after conversion to urea or
other products and the carbon skeleton is degraded to
CO2 releasing energy.
Metabolism of amino acids differs, but 3 common reactions:
– Transamination
– Deamination
– Decarboxylation
2
Transamination
In transamination
• Amino acids are degraded in the liver.
• An amino group is transferred from an amino acid
to an -keto acid, usually -ketoglutarate.
• The reaction is catalyzed by a transaminase or
aminotransferase.
•
• A new amino acid, usually glutamate, and a new
-keto acid are formed.
Transamination reactions
Enzymatic Transamination
• Typically, -ketoglutarate
accepts amino groups
• L-Glutamine acts as a
temporary storage of nitrogen
• L-Glutamine can donate the
amino group when needed for
amino acid biosynthesis
• All aminotransferases rely on
the pyridoxal phosphate
cofactor
Amino Group Transfer - Aminotransferase
Enzymatic removal of -amino groups (transaminase
/aminotransferases - named for amino donor
i.e. Ala aminotranferase removes amino group from Ala)
• Ping-pong
kinetics of
aspartate
transaminase (next slide)
(from previous slide)
Transamination
The 3-C -keto acid pyruvate is produced from alanine, cysteine, glycine, serine, & threonine.
Alanine deamination via Transaminase directly yields pyruvate.
alanine -ketoglutarate pyruvate glutamate
Aminotransferase (Transaminase)
COO
CH2
CH2
C
COO
O
CH3
HC
COO
NH3+
COO
CH2
CH2
HC
COO
NH3+
CH3
C
COO
O + +
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.
aspartate -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 + +
The Amino
Group is
Removed
From All
Amino
Acids First
12
Oxidative Deamination
Oxidative deamination
• Removes the amino group as an
ammonium ion from glutamate.
• Provides -ketoglutarate for
transamination.
Oxidative Deamination • Glutamate formed by transamination reactions
is deaminated to -ketoglutarate
• Glutamate dehydrogenase - NAD+ or NADP+ is coenzyme
• Other AA oxidases - (liver, kidney) low activity
It is one of the few enzymes that can use NAD+ or NADP+ as e acceptor.
Oxidation at the -carbon is followed by hydrolysis, releasing NH4
+.
OOC
H2
CH2
C C COO
O
+ NH4+
NAD(P)+
NAD(P)H
OOC
H2
CH2
C C COO
NH3+
Hglutamate
-ketoglutarate
Glutamate Dehydrogenase
H2O
Glutamate Dehydrogenase catalyzes a major reaction that effects net removal of N from the amino acid pool.
Summarized above:
The role of transaminases in funneling amino N to glutamate, which is deaminated via Glutamate Dehydrogenase, producing NH4
+.
Amino acid -ketoglutarate NADH + NH4+
-keto acid glutamate NAD+ + H2O
Transaminase Glutamate Dehydrogenase
Non-oxidative deamination
• Amino acids such as serine and
histidine are deaminated non-oxidatively
• The other reactions involved in the
catabolism of amino acids are
decarboxylation,
• transulfuration, desulfuration, dehydration
etc.
DEAMIDATION
• The amino acid, which contains an amide
linkage with ammonia at the γ-carboxyl,
degraded by process of deamidation.
• E.g, conversion of asparagine to aspartate
by removal of alpha amino group.
Decarboxylation
The decarboxylation process is important since the products of
decarboxylation
• reactions give rise to physiologically active amines.
The enzymes, amino acid decarboxylases are pyridoxal phosphate
dependent enzymes.
• Pyridoxal phosphate forms a Schiff's base with the amino acid so
as to stabilise the -carbanion formed by the cleavage of bond
between carboxyl and -carbon
• atom.
•
• The physiologically active amines epinephrine, nor-epinephrine,
dopamine,
• serotonin, -amino butyrate and histamine are formed through
decarboxylation of the corresponding precursor amino acids.
Transmethylation
• Resynthesis of methionine:
• Homocysteine accepts a methyl group from N5-
methyltetrahydrofolate (N5-methyl-THF)
requiring methylcobalamin, a coenzyme derived
from vitamin B12.
•
• The methyl group is transferred from the B12
derivative to homocysteine, and cobalamin is
• recharged from N5-methyl-THF.
Excretory
Forms of
Nitrogen
Fate of Individual Amino Acids
• Seven to acetyl-CoA – Leu, Ile, Thr, Lys, Phe, Tyr, Trp
• Six to pyruvate – Ala, Cys, Gly, Ser, Thr, Trp
• Five to -ketoglutarate – Arg, Glu, Gln, His, Pro
• Four to succinyl-CoA – Ile, Met, Thr, Val
• Two to fumarate – Phe, Tyr
• Two to oxaloacetate – Asp, Asn
Summar
y of
Amino
Acid
Cataboli
sm
NITROGEN BALANCE
Nitrogen balance = nitrogen ingested - nitrogen excreted
(primarily as protein) (primarily as urea)
Nitrogen balance = 0 (nitrogen equilibrium)
protein synthesis = protein degradation
Positive nitrogen balance
protein synthesis > protein degradation
Negative nitrogen balance
protein synthesis < protein degradation
UREA CYCLE
Detoxification
Of ammonia ()
REGULATION OF UREA CYCLE:
N-Acetylglutamate is an essential activator for carbamoyl phosphate
synthetase I—the rate-limiting step in the urea cycle
N-Acetylglutamate is synthesized from acetyl coenzyme A and glutamate by
N-acetylglutamate synthase in a reaction for which arginine is an activator.
UREMIA
urea and other waste products, are retained in the blood.
Early symptoms include anorexia , lethargy ,fatigue, nausea, vomiting, cold,
bone pain, itch, shortness of breath,, and late symptoms can include decreased
mental acuity and coma. when the glomerular filtration rate, a measure of
kidney function, is below 50% of normal.[2]
Uremia can also result in uremic pericarditis. There are many dysfunctions
caused by uremia affecting many systems of the body, such as blood (lower
levels of erythropoietin), sex (lower levels of testosterone/estrogen), and bones
(osteoporosis and metastatic calcifications).
Uremia can also cause decreased peripheral conversion of T4 to T3, producing
a functionally hypothyroid state.
Azotemia:
Refers to high levels of urea, but is used primarily when the abnormality
can be measured chemically but is not yet so severe as to produce
symptoms.
Uremia is the pathological manifestations of severe azotemia.
Hyperammonemia
The capacity of the hepatic urea cycle exceeds the normal rates of
ammonia generation .
The levels of serum ammonia are normally low (5–35 μmol/L).
CAUSES:
liver function is compromised, due to genetic defects of the urea cycle or
liver disease.
blood levels can rise above 1,000 μmol/L.
Such hy per ammon emia is a medical emergency, because ammonia
has a direct neurotoxi effect on the CNS.