Transcript Lecture 33 - University of Arizona

Amino Acid Metabolism 2:
Amino acid biosynthesis, amino acids are
metabolites, metabolic genetic disorders
Bioc 460 Spring 2008 - Lecture 39 (Miesfeld)
Roundup Ready soybeans
are resistant to glyphosate
and are sold by Monsanto
Albinism is caused by
mutations in the tyrosinase
gene which is required for
pigment biosynthesis
It was thought at one time
that Count Dracula may have
suffered from porphyria
Key Concepts in Amino Acid Metabolism
• Plants and bacteria synthesize all twenty amino acids, humans can only
synthesize about half of the twenty amino acids.
• In general, the more complex amino acids are essential amino acids in
humans as they require enzymes that have been lost from the human
genome over evolutionary time.
• The herbicide glyphosate (RoundUp) is an inhibitor of the Shikimate
Pathway responsible for the synthesis of aromatic amino acids.
• Numerous genetic diseases are caused by defects in amino acid
metabolic pathways; genetic diseases can be due to recessive or
dominant mutations.
Overview of Amino Acid Biosynthesis
The carbon skeletons of all twenty amino acids are derived from just
seven metabolic intermediates, that together, are found in three
metabolic pathways. These include:
1) three glycolytic pathway intermediates; 3-phosphoglycerate,
phosphoenolypyruvate, and pyruvate,
2) two pentose phosphate pathway intermediates; ribose 5phosphate and erythrose 4-phosphate
3) two citrate cycle intermediates; -ketoglutarate and
oxaloacetate.
Overview of Amino
Acid Biosynthesis
Arginine is listed as an essential amino acid
because humans require arginine in their diet to
support rapid growth during childhood and
pregnancy, even though it is made by urea cycle.
Tyrosine is also highlighted because this conditional
nonessential amino acid is made in humans from the
essential amino acid phenylalanine.
In general, the
structures of the
essential amino
acids are more
complex than the
nonessential amino
acids which is
reflected in the
number of enzymatic
reactions required for
synthesis.
It is critical that metabolic
flux through various amino
acid biosynthetic pathways
be tightly regulated by
feedback inhibition to
provide the required
proportions of each amino
acid in response to cellular
needs.
Overview of Amino Acid Biosynthesis
The biosynthesis of three nonessential amino acids (alanine, aspartate and
asparagine), and six essential amino acids (methionine, threonine, lysine,
isoleucine, valine and leucine) in E. coli involves two interconnected pathways
utilizing pyruvate and oxaloacetate.
One of the most widely
used herbicides is
glyphosate, the active
ingredient in Roundup®.
Glyphosate is a
competitive inhibitor of
the enzyme EPSP
synthase which is
required to convert
shikimate 3-phosphate to
EPSP.
Since animals do not
have the shikimate
pathway enzymes,
Roundup is an animal
safe herbicide.
Do you think
glyphosate works
faster in the summer
or winter? Explain.
Roundup Ready Crops are Glyphosate-Resistant
Monsanto developed
glyphosate-resistant crop
plants so that farmers
could spray their transgenic
crops with Roundup (also
made by Monsanto) and
kill weeds that reduce crop
yields without harming the
crop plants.
The first glyphosateresistant crop plant
developed was a strain of
soybeans marketed as
Roundup Ready®
soybeans.
Amino Acids as Metabolic Precursors
Because of the nitrogen content
of amino acids (the -amino
group), they are also used as
metabolic precursors for
numerous biomolecules,
including:
• Heme groups (hemoglobin and
cytochromes),
• Nucleotide bases (purines and
pyrimidines)
• Signaling molecules
(neurotransmitters, hormones,
nitric oxide).
Amino Acids as Metabolic Precursors
Tyrosine is the precursor to several important molecules in metabolic
signaling and neurotransmission, including epinephrine and dopamine.
Tyrosine is also the
precursor to pigment
molecules called
melanins that are
produced from
dopaquinone.
Amino Acids as Metabolic Precursors
Natural loss of hair color occurs as a result of aging when melanin
production shuts down in human melanocytes located near the
base of hair follicles and these defective cells are not replaced as
they normally are in younger individuals.
Gray hair can be colored by treating it with a mixture of hydrogen
peroxide and an ammonia based solution containing artificial
pigments.
Inborn Errors of Metabolism: Genetic Disease
A genetic defect in the gene encoding phenylalanine hydroxylase is
responsible for the metabolic disease phenylketonuria (PKU).
The clinical symptoms of
PKU are caused by the
accumulation of
phenylalanine in the blood
that is 30-50 times higher
than normal.
NutraSweet contains a phenylalanine derivative
Phenylketonuriacs have to
be careful to avoid
processed foods and
beverages containing the
food additive aspartame
(aspartyl-phenylalanine
methyl ester).
PKU is an autosomal recessive genetic disease
The phenylalanine
hydroxylase gene is
located on chromosome
12 making it an
autosomal recessive
genetic disease.
What would the probability
be of having a PKU
afflicted child if the mother
was normal (PP) and the
father was a carrier (Pp)?
Type 1 albinism is an autosomal recessive
genetic mutation in the tyrosinase gene
Interestingly, individuals with
phenylketonuria can have light
skin and hair at birth because of
low levels of tyrosine.
However, phenylketonuriacs are
not albinos because they obtain
sufficient amounts of tyrosine in
their diets to support melanin
biosynthesis.
Why is PKU treatable, but albinism is not, even though both
are the result of genetic mutations in enzymes?
Congenital porphyrias effect heme biosynthesis
and can be the result of dominant mutations
How might a mutant protein cause a dominant (gain of function) phenotype?
Congenital porphyrias effect heme biosynthesis
and can be the result of dominant mutations
It is thought that King George III of England may have suffered from
acute intermittent porphyria based on descriptions of his health that
were written at the time of the American Revolution.
Congenital porphyrias effect heme biosynthesis
and can be the result of dominant mutations
A more rare form of porphyria is congenital erythropoietic porphyria that is
characterized by red urine, reddish brown fluorescent teeth, sensitive to
sunlight, and otherwise sickly (anemic).
The Legend of the Vampires Lives on in the
Imaginative Minds of Biochemists Everywhere