AMINO ACID METABOLISM

INTRODUCTION

Body proteins represent a significant proportion of potential energy reserves

Under normal circumstances, they are not used for energy production

In an extended fast, however, muscle protein is degraded to amino acids

For the synthesis of essential proteins

To keto acids for gluconeogenesis to maintain blood glucose

concentration

This accounts for the loss of muscle mass during fasting

Conversion of the carbon skeletons of the common L--amino acids amphibolic

intermediates

Metabolic diseases or inborn errors of metabolism associated with these

processes if left untreated can result in irreversible brain damage and early
mortality

Prenatal or early postnatal detection and timely initiation of treatment

thus are essential

Many of the enzymes are detected in cultured amniotic fluid cells

which facilitates prenatal diagnosis by amniocentesis

Screening tests

Lower catalytic efficiency (Vmax or Km)

Alter the affinity for an allosteric regulator

Treatment

Primarily of feeding diets low in the amino acids whose

catabolism is impaired

Amount of nitrogen is relatively constant except during growth

No storage form of nitrogen reserve; free amino acid

Liver is the major site of nitrogen metabolism

Urea synthesis

Synthesis of most non-essential amino acids

Degradation of large part of amino acids

All tissues have some capability for synthesis of the non-essential amino acids

During dietary surplus

Potentially toxic nitrogen of amino acids via transaminations and

deamination (Glutamate Dehydrogenase) Urea

Carbon skeletons are generally conserved as carbohydrate via

gluconeogenesis or as fatty acid via fatty acid synthesis pathways

During starvation reduced carbon skeleton oxidized to CO2 and H2O +

energy production
Metabolic Relationships among Amino
Acids

Free amino acids pool is derived

from body proteins and the diet

Amino acids are precursors of

important biomolecules

Serve as a carbon source for

central metabolism
gluconeogenesis, lipogenesis,
and energy production
Major Steps in Amino Acid Catabolism

Removal of amino group

Transamination

Oxidative deamination: Removal of amino group from glutamate to

release ammonia

Other deamination processes

Urea cycle: Conversion of ammonia (NH3) to urea

Metabolic breakdown of carbon skeleton to
Alanine + -Ketoglutarate
generate common intermediates
Glutamate
catabolized to CO2 or used in anabolic
pathways to be stored as glucose or fat

Pyruvate +

Amino Acid Reactions

Transamination

Most important

Transfer of amino group to -keto

acid

Requires Pyridoxal Phosphate

(PLP)

Synthesis
Broad Substrates
(Cannot act with
of nonionizable side
essential
amino acids

Degradation of most amino acids

Exchange of amino group

Most transaminases require Ketoglutarate or Glutamate as one of

the reacting pairs

Exception:
Schiff base, imine
Lysine,
intermediate hydrolyzes
to form keto acid and
Threonine,
ammonia
Proline

Glucogenic/Ketogenic Amino Acids

Amino acids fall into three categories

Glucogenic

Net production of pyruvate or TCA cycle intermediates

precursors to glucose via gluconeogenesis

Alanine, Arginine, Aspartate, Cysteine, Glutamate, Glycine,

Histidine, Methionine, Proline, Serine, Valine

Ketogenic

Giving rise only to acetyl CoA or acetoacetyl CoA

Leucine, Lysine
Glucogenic and Ketogenic

Give rise to both glucose and fatty acid precursors

Phenylalanine, Isoleucine, Threonine, Tyrosine, Tryptophan

Catabolism of the Carbon Skeleton of Amino Acids

All twenty common amino acids are converted to only seven compounds
1. Pyruvate
2. -Ketoglutarate
3. SuccinylCoa
4. Fumarate
5. Oxaloacetate
6. Acetyl CoA
7. Acetoacetyl CoA
Glycine and All Three-Carbon Amino Acids are Converted to Pyruvate

Deficiency of

Proline

GPT, PLP

[O2]

Cysteine
Pyruvate + SO3-2

Transaminase/Desulfin

Cyssulfinate
ase

Transamina
se

3-Mercaptopyruvate

S
transferas

Glycine Cleavage

Liver mitochondria: GlycineComplex

CO2 and NH4+
ThrAldolas

Threonine e

Acetaldehyde
Dehydrogen
ase

Glycine

H4F

N5, N10-methylene H4F

SerHydroxymeth
yl
THF

Acetyl

Thiokinas
CoAe

Acetate

Serine

Deficiency of

HistidinaseHistidinemia

UrocanaseUrocanic Aciduria
Histidine Loading Test Folic Acid Level

Nonpolar Amino Acids Methionine, Valine, and Isolecuine are Converted to

Succinyl CoA

Four-Carbon Amino Acids are Converted to Oxaloacetate

Catabolism of Methionine

Five-Carbon Amino Acids are Converted to -Ketoglutarate

Dehydrogenase Type I Hyperprolinemia

Glutamate--semialdehyde Dehydrogenase
Type II Hyperprolinemia
Ornithine Aminotransferase Gyrate atrophy
of retina

Moderately elevated levels of

homocysteine in plasma implicated in
the development of cardiovascular
disease and cerebrovascular ischemic
episodes

Arthritis
Darkening of urine
on standing

Catabolism of Branched Chain Amino Acids

Catabolism of Tryptophan

Via the KynurenineAnthranilate pathway

Tryptophan Pyrrolase
or Tryptophan
Oxygenase is a
hemoprotein

Kynureninase
requires pyridoxal

Maple Syrup Urine Disease

Branched Chain Ketonuria

Branched chain keto acid

dehydrogenase
deficiency

Mental retardation

Ketoacidosis

Short life span

Catabolism
of
Phenylalanine and Tyrosine

phosphate

Tryptophan
load
diagnostic
of Vitamin
B6
deficiency
Hartnup
disease reflects impaired intestinal and renal
transport of Trp

Phenylketonuria (PKU)

Deficiency of
Phenylalanine
Hydroxylase
Autosomal
recessive

Neurological
signs and
symptoms

Mousy urine
(Phenylacetate)

Alternative pathways for

the catabolism of
phenylalanine in patients
with phenylketonuria

The end
product
phenylpyruvate
accumulates in
liver, blood, and
urine
Phenylacetate and phenyllactate are also found in urine

Alkaptonuria

Homogentisate Oxidase deficiency

Autosomal recessive

General pigmentation of connective tissue (onchronosis)

Catabolism of

Overview of Amino Acid Carbon Skeleton Catabolism

Lysine

Aspartate
Glutamin
e
Purine
Pyrimidin

CONVERSION OF AMINO ACIDS TO SPECIALIZED PRODUCTS

INTRODUCTION

Certain proteins contain amino acids post-translationally modified specific

functions

Carboxylation of Glutamate (Glu) -Carboxyglutamate (Gla) Ca2+ binding

Hydroxylation of Proline triple helix and the hydroxylation of Lysine

modification and cross-linking stabilizes maturing
collagen fibers

Roles as precursors of biologic materials

Heme, purines, pyrimidines, hormones,

active amines, neurotransmitters

Polyamines
Stabilized

Arginin
e

Carnosine (-alanyl-histidine) and

homocarnosine (-aminobutyrylhistidine) are major constituents of excitable tissues, brain, and skeletal muscle


Nitric Oxide (NO)

Is a short-lived signal molecule with diverse roles in different cell types

Vasodilation, Regulation of smooth muscle contraction, Gene

transcription
Neurotransmission in CNS, Stimulation of penile erection
Nonspecific host defense mechanisms and macrophage-mediated
killing inhibits the proliferation of tumor cells and microorganisms
Induction of apoptosis (programmed cell death)