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Amino Acid Metabolism 2: Amino acid biosynthesis, amino acids are metabolites, metabolic genetic disorders

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Bioc 460 Spring 2008 - Lecture 39 (Miesfeld) ... King George III of England may have suffered from acute intermittent porphyria ... – PowerPoint PPT presentation

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Title: Amino Acid Metabolism 2: Amino acid biosynthesis, amino acids are metabolites, metabolic genetic disorders


1
Amino Acid Metabolism 2Amino acid biosynthesis,
amino acids are metabolites, metabolic genetic
disorders
Bioc 460 Spring 2008 - Lecture 39 (Miesfeld)
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
Roundup Ready soybeans are resistant to
glyphosate and are sold by Monsanto
2
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.

3
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
  • three glycolytic pathway intermediates
    3-phosphoglycerate, phosphoenolypyruvate, and
    pyruvate,
  • two pentose phosphate pathway intermediates
    ribose 5-phosphate and erythrose 4-phosphate
  • two citrate cycle intermediates ?-ketoglutarate
    and oxaloacetate.

4
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.
5
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.
6
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.
7
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.
8
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.
9
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
glyphosate-resistant crop plant developed was a
strain of soybeans marketed as Roundup Ready
soybeans.

10
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).

11
Amino Acids as Metabolic Precursors
Tyrosine is the precursor to several important
molecules in metabolic signaling and
neurotransmission, including epinephrine and
dopamine.

12
Tyrosine is also the precursor to pigment
molecules called melanins that are produced from
dopaquinone.

13
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.

14
Inborn Errors of Metabolism Genetic Disease
A genetic defect in the gene encoding
phenylalanine hydroxylase is responsible for the
metabolic disease phenylketonuria (PKU).

15
The clinical symptoms of PKU are caused by the
accumulation of phenylalanine in the blood that
is 30-50 times higher than normal.

16
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).

17
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)?
18
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?
19
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?
20
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.

21
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).

22
The Legend of the Vampires Lives on in the
Imaginative Minds of Biochemists Everywhere
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