Professor Todd Holyoak is an expert in the dynamic aspects of the enzyme structure-function relationship, or “conformational plasticity” in enzymology and how these dynamic aspects of enzyme structure can be altered/influenced to alter and enzyme function. Currently, the Holyoak lab is exploring the structure-function relationship in several diverse enzyme families with a current focus upon the GTP-dependent phosphoenolpyruvate carboxykinases (PEPCK) and the IgA1 protease family of bacterial proteins.
PEPCK
is
an
important
cataplerotic
enzyme,
essential
to
maintaining
blood
glucose
levels
in
humans
and
other
mammals;
flux
through
PEPCK
contributes
to
the
fasting hyperglycaemia
seen
in
patients
with
both
Type
1
and Type
2
diabetes,
and
has
been
postulated
to
be
a
factor
in
other
significant
biological
processes
such
as
cancer
and
aging.
While
his
work
is
focused
upon
the
basic
principles
of
the
structure-function
relationship,
these
studies
may
also
contribute
to
the
ability
to
regulate
PEPCK
in
the treatment
of
disease
and
biological
disfunction.
Human immunoglobulin A1 (IgA1) is an antibody that plays an important role in the immune protection of mucous membranes. Due to this fact, it is not surprising that infectious microbes generate IgA1 proteases that cleave the protective IgA1 antibodies which can lead to disease as a result of the initial bacterial colonization of the mucosa. Professor Holyoak with collaborator and WIN member Professor Scott Taylor from the Department of Chemistry are collaborating on the project, “Structural Studies of Bacterial IgA1 Proteases”, which may lead to the development of novel antibiotics for common but serious infections caused by the bacteria that produce IgA1 proteases.
While its protective role is essential to human health, IgA1 is also associated with several autoimmune disorders, including celiac disease, IgA vasculitis, and Berger’s disease. Also known as IgA1 nephropathy, Berger’s disease occurs when IgA1 deposits in the kidneys resulting in inflammation and eventual kidney failure. Presently there is no cure for the disease however, it has been demonstrated that IgA1 proteases may represent an effective treatment strategy. Professor Holyoak and his team are working to better understand IgA1 protease structure and function with the ultimate goal being the ability to design novel IgA protease enzymes for use in the treatment of diseases resulting from aberrant IgA1 deposition such as IgA nephropathy.
For more stories like this one please see our 2018-2019 Annual Report.