Page 13 - Periodic Issue 02

Coping with Low O xygen –

Rainbows, Rapid Expansion An Enzymatic Perspective on

Human Health

Dr. Emily Flashman disease and anaemia. Reducing HIF levels in cancer is more
of a challenge, and requires making the oxygen-sensing
Royal Society Dorothy enzymes more active at lower oxygen concentrations.
Intriguingly, we and others have found that ascorbic acid
Hodgkin Research is able to prolong HIF hydroxylase activity, suggesting that
Fellow Vitamin C may have a role as an anti-cancer agent as
has been postulated, but never proven, in the scientific
Oxford Cancer community for many years.
Research Centre But these oxygen-sensing HIF hydroxylases are not the
Development Fund only enzymes in cells. Our bodies are full of molecules vital
for various reactions of life, and many of them also require
oxygen. This begs the question, what else goes on, or
Our bodies use oxygen to make the energy required to
drive life: cell division, growth, movement, thought. Without rather stops going on, when oxygen levels drop? And what
oxygen, vital biochemical processes fail and cells quickly consequence does this have for tumour development?
die. So what happens when we don’t get as much oxygen In particular, my group looks at the ways in which oxygen
as we need? If oxygen deprivation is prolonged, e.g. living at controls the activity of enzymes involved in epigenetic
high altitude or participating in endurance sport, our bodies regulation, thus affecting which of our genes are turned on
can respond with a signalling molecule called ‘HIF’, which or off at any given time. This is important in cancer: different
triggers adaptations to increase oxygen delivery and improve patterns of gene expression can affect growth and survival. It
metabolic efficiency. HIF levels are normally kept low by a set is fascinating work, and we hope it will contribute to a better
of oxygen-dependent enzymes which hydroxylate specific understanding of tumour biology from which more targeted
proline amino acids in HIF - this hydroxylation acts as a signal and effective treatments can be developed.
for HIF to be degraded by the cell. When oxygen levels
drop, HIF levels rise to help the body cope. The activity of
these HIF hydroxylases correlates closely with oxygen levels,
making them very efficient oxygen sensors. In molecular
terms, the reaction of the HIF hydroxylases with oxygen is
tightly controlled, and understanding how this is achieved is
one of the key interests in my group.

A number of diseases result in low oxygen levels and
thus elevated HIF - tumours, for example, are often poorly
oxygenated because the cancerous cells are growing
so rapidly they outgrow their own blood supply. The
consequence of increased HIF levels in cancer cells is
aggressive tumour growth and poor prognosis. On the
other hand, in cardiovascular disease, raising HIF levels can
improve outcomes, e.g. by promoting blood vessel formation
(and thus oxygen delivery) in damaged heart tissue, helping
to prevent long term damage to the heart muscle.

Regulation and manipulation of HIF is therefore an area of
research with potentially great benefits. An effective way
to manipulate HIF is via the oxygen-sensing enzymes that
control HIF levels. Indeed, inhibitors of these enzymes are
being investigated as potential treatments for cardiovascular

13
Periodic
The Magazine of the Department of Chemistry