Therapeutic applications of Phenylalanine ammonia lyase and Phenylalanine Hydroxylse in phenylketonuria
1. RINAD A. ALJOHANI
THERAPEUTIC APPLICATIONS OF
PHENYLALANINE AMMONIA LYASE AND
PHENYLALANINE HYDROXYLSE IN
PHENYLKETONURIA
2. WHAT IS PHENYLKETONURIA
• Phenylketonuria is an inherited disorder of amino
acid metabolism caused by phenylalanine
hydroxylase deficiency
• It is characterized with high levels of the amino acid
phenylalanine in the blood
• The patients urine has a characteristic “mousey” odor
• If not treated it would cause behavioral problems,
seizures, mental retardation, and failure to grow.
3. WHAT IS PHENYLKETONURIA
• Early diagnosis of PKU is important
because a lot of the central nervous
system symptoms can be avoided by
controlled level of (Phe) through strict diet
with no very low protein intake. Although,
simple dietary restriction of (Phe) levels
will not reverse the central nervous system
effects due to neurotransmitters
deficiencies.
4.
5. PHENYLALANINE HYDROXYLSE
• 1. What is Phenylalanine Hydroxylse
• Phenylalanine Hydroxylse PAH is an enzyme
responsible for the conversion of the amino acid
phenylalanine (phe) to tyrosine
• 2. Structure Phenylalanine Hydroxylse
• PAH consist of two or four identical subunits, present
in equilibrium it has two forms and is is regulated by
phenylalanine (phe), tetrahydropiopterin (BH4), and
phosphorylation
8. FUNCTION OF PHENYLALANINE
HYDROXYLSE
• It has two binding sites, a catalytic site, and a
regulatory site. The binding site of which is located
near the hinge domain might be the factor that
causes the drastic change in the enzyme’s shape
which will result in (Phe) substrate cleavage.
• In order for the PAH to catalyze the (Phe) in the
dephosphorylated state, (Phe) levels must be
significantly high enough for this step to occur.
9. DIETARY TREATMENT OF
PHENYLKETONURIA
• 1. Current treatment of PKU
• For decades patients with PKU had to maintain their (Phe)
levels through their diet. The primary therapeutic approach has
been to lower the elevated (Phe) concentrations to be within
the therapeutic range as higher (Phe) concentrations are
considered toxic
• There have been newer approaches in dietary management of
PKU such as Tetrahydrobiopterin and other pharmacological
chaperones, large neutral amino acids (LAAs), and
Glycomacropeptide.
10.
11.
12. MATERNAL PKU:
• When female patients of PKU become pregnant while
their dietary levels of (Phe) exceed the required low
range the offspring will get affected with “maternal
PKU Syndrome”.
• Increased levels of (Phe) in the blood will cause
mental retardation, intrauterine growth retardation
• dietary control of (Phe) levels in the blood must begin
prior to conception and be maintained through-out the
pregnancy to avoid damaging the fetus.
13. A NEW ERA FOR THE TREATMENT OF
PHENYLKETONURIA
• So far treatment for PKU has been Successful in many
ways but something better is needed. New treatments
for PKU are emerging right now. Such as Sapropterin
which is a synthetic form of tetrahydrobiopterin, the
cofactor in the PAH reaction. There is also enzyme
replacement therapy (ERT) with two enzyme systems
that are being developed for PKU treatment (PAH
enzyme and the Phe-degrading enzyme
phenylalanine ammonia-lyase (PAL))
14. 1. TREATMENT OF PKU USING
PHENYLALANINE AMMONIA LYASE
• PAL is an enzyme substitution therapy that break down (Phe)
into ammonia and trans-cinnamic acid
• PAL exists in bacteria and yeast; not in mammals.
• In therapy in order to reduce its immunogenicity it is
conjugated with polyethylene glycol (PEG).
• Subcutaneous administration of PAL result in lowering plasma
and brain (Phe) concentrations. However the metabolic effect
was not sustained due to an immune response
15. . TREATMENT OF PKU USING
PHENYLALANINE AMMONIA LYASE
• Scientists have chemically modified PAL by
pegylation producing a form of PAL with higher
more prolonged half-life, better specific activity,
and reduced immunogenicity to not cause serious
immune reactions.
16. • PAL therapy is more favorable than PAH
because it requires no cofactors for degrading
the (Phe) and its metabolites has low toxicity
levels and no embryotoxic effects. in
experimental animals, The PAL was very stable
under wide range of temperatures.
18. 2. ENZYME REPLACEMENT THERAPY
USING PAH
• Since PAH is the enzyme involved in Phe
metabolism, it comes as a natural choice for
enzyme based therapeutics in the
management of PKU.
19. • PAH is not an autocatalytic enzyme, it requires
several co-factors to function which make the
therapy quite complex and challenging because
it would mean having to maintain a multi-
component enzyme in a stable state which is a
herculean task.
20. CONCLUSIONS
• The future is very bright for PKU patients with the considerable
advances in ERT to treat PKU. Multiple treatment options are
now available
• These include the use of various forms of PAH, PEGylated
PAH as well as the Phe degrading enzyme PAL.
• Although a great deal of work has been conducted to date,
there are still problems to overcome, including the stability of
the enzymes, consistency of response, and avoiding immune
responses.
