AMINO ACID METABOLISM

LECTURE ONE

Shandele Ginnethon

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 INTRODUCTION

• Plants and microorganisms can synthesize all of the 20

standard amino acids.

• Mammals, however, cannot synthesize all 20 and must obtain

some of them in their diet.

• Those amino acids that are supplied in the diet are referred to
as essential, whereas the remainder that can be synthesized
by the organism are termed non-essential.

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 INTRODUCTION

Amino acids are also a source of intermediates and

some biologically essential molecules other than
proteins.

EXAMPLES
• Pyruvate can be formed from glycine, serine,
alanine, cysteine, threonine, 4-hydroxyproline.

• Acetyl CoA can be formed from tyrosine,

phenylalanine, lysine and tryptophan.
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 Catabolism of Amino Acid Nitrogen
• Excess amino acids can not be stored nor are they excreted
as such.
• The amino acids are metabolized such that the amino groups
are removed by transamination or oxidative deamination
• and the remaining carbon skeletons are used as
intermediates for other reactions.
• The carbon skeletons of the 20 standard amino acids are
funneled into only seven molecules:
Pyruvate, acetyl CoA, acetoacetyl CoA, α-ketoglutarate,
succinyl CoA, fumarate & oxaloacetate. Fish are
ammonotelic because they excrete amino groups as ammonia.

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• Birds and amphibians are uricoteric because they excrete
amino groups as uric acid AND mammals are ureotelic
because they excrete urea. Ammonia is toxic to the nervous
system and uric acid results in crystal deposition.
• So to avoid these effects humans evolved a capacity to
convert their nitrogenous waste to the highly soluble
nontoxic urea
Four Stages of Urea Biosynthesis.
1. Transamination
2. Oxidative deamination of glutamate
3. Ammonia transport
4. Reactions of the urea cycle
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• Amino acids that are degraded to pyruvate, α-ketoglutarate,
succinyl CoA, fumarate and oxaloacetate are termed
glucogenic as they can give rise to the net synthesis of
glucose.

• This is because the citric acid cycle intermediates and

pyruvate can be converted into phosphoenolpyruvate and then
into glucose via gluconeogenesis
• In contrast, amino acids that are degraded to acetyl CoA or
acetoacetyl CoA are termed ketogenic because they give rise
to ketone bodies; the acetyl CoA can also be used to
synthesize lipids
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• Of the standard set of 20 amino acids, only Leu and Lys are
solely keto-genic.

• Ile, Phe, Trp and Tyr are both ketogenic & glucogenic as
some of their carbon atoms end up in acetyl CoA or
acetoacetyl CoA, whereas others end up in precursors of
glucose.

• The remaining 14 amino acids are classified as solely

glucogenic.

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 Urea Biosynthesis .
Transamination
• PROCESS by which the α-amino group of the amino acid is
removed.

• In this process the α-amino group of most amino acids is

transferred to α-ketoglutarate to form glutamate and the
corresponding α-keto acid; mostly occurs in liver.

• Glutamate then enters the mitochondria where it undergoes

oxidative deamination to release ammonia and reforms α–
ketoglutarate in the process.
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• Transamination is catalyzed by aminotransferases
• Coenzyme for aminotransferases is pyridoxal phosphate
[(PLP),which is derived from pyridoxine (vitamin B6)],
which is transiently converted into pyridoxamine phosphate
during transamination

• Through transamination, amino acids can transfer their amino

groups to keto acids like pyruvate and α–ketoglutarate to
form alanine and glutamate respectively.

• Alanine is a carrier of these amino groups from muscles to

the liver. 9
 Oxidative Deamination
• The α-amino groups that have been funneled into glutamate
from the other deamination of amino acids are then
converted into ammonia by the action of glutamate
dehydrogenase.

• This enzyme utilizes either NAD+ or NADP+ (unusual)

• In the biosynthesis of glutamate, the NADP+ form of the

coenzyme is used, whereas NAD+ is used in its degradation.
• Glutamate dehydrogenase consists of six identical subunits
and is subject to allosteric regulation-GTP and ATP are
allosteric inhibitors; GDP and ADP are allosteric activators.
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Oxidative deamination of Glu by Glu dehydrogenase

• OXIDATIVE DEAMINATION OCCURS IN THE

MITOCHONDRIA.i.e.Glutamate enters the mitochoindria where
nitrogen is released as ammonia through oxidative deamination

• Glutamine which carries amino groups from peripheral tissues is

also deaminated in the mitochondria to form glutamate which is
then metabolized as explained above. 11
 Formation of ammonia and its toxicity
• Ammonia produced by enteric bacteria and absorbed into the
portal venous blood and the ammonia produced by tissues are
rapidly removed from the circulation by the liver and
converted to urea.

• Should portal blood bypass the liver systemic blood ammonia

may rise to toxic levels.
WHERE THIS OCCURS
• In severe hepatic impairment
• cirrhosis where collateral circulation is established.
• Symptoms of ammonia toxicity include tremor, slurred
speech, blurred vision, coma, and ultimately death.
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• Ammonia formed upon deamination of glutamate and
glutamine is converted to the non-toxic form urea.

• Of the six amino acids involved in urea synthesis, N-acetyl

glutamate functions as an enzyme activator, remaining 5-
aspartate, arginine, ornithine, citrulline and
argininosuccinate function as carriers of atoms.

• Amino acids aspartate and arginine occur in proteins but

ornithine, citrulline and argininosuccinate do not occur in
proteins but play a role in urea synthesis
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 Urea
CO2 + NH4 Argininase
Carbamoyl 5
phosphate 1
Ornithine
synthase 1

Carbamoyl Ornithine Arginine

phosphate transcarbam
oylase 4
2 Fumarate
Argininosuccinase

Citrulline Argininosuccinate
Argininosuccinic
acid synthase
Rate limiting
enzyme 3

Aspartate
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 Metabolic Disorders Associated With Each
Reaction Of The Urea Cycle
• All defects in urea synthesis results in ammonia intoxication
• Intoxication is more severe if block occurs at reactions 1 or 2.
• Clinical symptoms: vomiting, avoidance of high protein diet,
irritability, lethergy and mental retardation
1. Hyperammonemia type 1: Carbamoyl phosphate synthase 1
deficiency
2. Hyperammonemia type 2 Ornithine transcarbamoylase
deficiency
3. Citrullinemia Arginosuccinate synthase deficiency
4. Argininosuccinicaciduria Argininosuccinase deficiency
5. Hyperargininemia Arginase deficiency 15
 Regulation of the urea cycle-at two levels
1. The flux of nitrogen through the urea cycle varies with the
organism's diet:
 On high protein diet, the carbon skeletons of amino acids are
used for fuel and excess amino groups are converted into urea.
 During prolonged starvation, breakdown of muscle protein
supplies much of the metabolic energy and this results in
increased urea production.
 All five enzymes involved in urea production are synthesized
at higher rates in starving animals and in animals on high-
protein diet
2. Allosteric regulation of carbamoyl phosphate synthetase I.
This enzyme is activated by N-acetylglutamate
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