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The Central
Dogma of
Inborn Errors of Metabolism
• Archibald Garrod (British, 18571936)
• The relationship between
genes and proteins was first
proposed by Garrod in 1908
• Garrod, a prominent physician
at St. Bartholomew's Hospital in
London, understood both the
new science of biochemistry
and the emerging discipline of
• He studied a harmless but rare disorder in
the general population but frequent in
children of first-cousin marriages:
• A patient with this disorder produces urine
that when exposed to air turns distinctively
dark, because these people lack the
enzyme found in normal individuals who
are able to convert the reddening agent,
alkapton, to another substance
• Following
Mendel’s laws,
concluded that
alkaptonuria is a
disorder, not the
result of a
bacterial infection
as was
Garrod cont.
• He observed that inherited diseases reflect
a patient's inability to make a particular
enzyme, which he referred to as “inborn
errors of metabolism”
• He further hypothesized that enzymes are
under the control of the hereditary
material, and thus an error in the DNA
resulted in an error in the enzyme.
• Garrod's hypothesis was ahead of its time
One gene-One Enzyme
• This proposal of the one
gene-one Enzyme
hypothesis was developed
by the Americans George
Beadle (1903-1989) and
George Wells Tatum (19091975) in 1938
• Beadle and Tatum hypothesized that if there
really was a one-to-one relationship between
genes and specific enzymes, it should be
possible to create genetic mutants that are
unable to carry out specific enzymatic reactions
• They exposed spores of Neurospora crassa (a
bread mold) to X-rays or UV radiation and
studied the resulting mutations
• The mutant molds had a variety of special
nutritional needs. Unlike their normal
counterparts, they could not live without the
addition of particular vitamins or amino acids to
their food
• Normal Neurospora requires only one vitamin
(biotin), but mutants were created that also
required thiamine or choline
Arginine Biosynthesis
• What is the order of the reactions in arginine biosynthesis.
Beadle and Tatum cont.
• Genetic analysis showed that each mutant
differed from the original, normal type by
only one gene
• Biochemical studies showed that the
mutants seemed to be blocked at certain
steps in the normal metabolic pathways
• Their cells contained large accumulations
of the substance synthesized just prior to
the blockage point, just as Garrod's
patients had accumulated alkapton
Beadle and Tatum cont.
• As Beadle and Tatum had predicted, they
created single gene mutations that
incapacitated specific enzymes, so that
the molds with these mutations required
an external supply of the substance that
the enzyme normally produced, and the
substance that the enzyme normally used,
piled up in the cell
• These results confirmed their one geneone enzyme hypothesis
• They received the 1958 Nobel Prize in
Physiology and Medicine
Vernon Ingram
• In 1956, Ingram a protein
chemist developed a technique
called fingerprinting, which maps
on paper the various amino acids
in a protein sample.
• By comparing the fingerprints
of sickle cell and normal hemoglobin, Ingram found that one
spot differed between the two fingerprints.
Ingram cont.
• He concluded that normal and sickle cell
hemoglobin have a small difference in
their amino acid sequences.
• From this conclusion we now know that
each gene on the DNA will code for one
polypeptide or protein.
...... Central Dogma
One Gene – One Polypeptide
The Big Picture