The production of glucose from
non-carbohydrate sources fuels tuberculosis (TB) infection. This
metabolic pathway, known as gluconeogenesis, might be a good drug
target, according to new research from the Francis Crick Institute
and Weill Cornell Medical College in New York, USA.
The team identified a redundant
step, indicating a second unknown protein was acting in this TB
pathway. Consistent with this proposal, deletion of the first, well
known, enzyme had no effect in experimental infections, indicating
that a second enzyme was acting as its back-up.
Dr Luiz Carvalho of the Crick
explained: "Fatty acids are well accepted as one of the main food
sources for the Mycobacterium tuberculosis, the pathogen that
causes TB, during infection".
"The metabolic pathway known as
gluconeogenesis is therefore essential for the synthesis of
carbohydrate, nucleotides (the 'building blocks' of DNA and RNA)
and several amino acids (which make up proteins)."
The team investigated an ezyme
involved in gluconeogenesis called fructose 1,6 bisphosphate
phosphatase (FBPase). Their research combined bacterial, genetic,
microbiology and biochemical techniques with state-of-the-art
screening of metabolism products and mouse infection
experiments.
Unexpectedly they found that
deleting the gene for FBPase didn't affect growth in fatty acids,
indicating that either a new metabolic pathway or that an unknown
enzyme was acting to convert fatty acids into glucose.
The researchers went on to discover
a second FBPase (FBPase II) in M. tuberculosis. Further work
in mice showed that the genes for both FBPases needed to be deleted
to reduce TB infection, providing strong evidence that
gluconeogenesis is indeed an important metabolic pathway during TB
infection.
Importantly, when both genes
encoding FBPases are deleted, M. tuberculosis infection is cleared
from the host, emphasising the importance of gluconeogensis during
infection and its potential as a drug target.
Dr Carvalho said: "Our discovery
provides important information for ongoing drug discovery efforts
aimed at finding new compounds to treat human TB."
"Our study proves for the first
time that gluconeogenesis is taking place during infection, and
therefore indicates that ideal gluconeogenic inhibitors might be
sought as new drugs. However we also demonstrate that due to
redundancy, FBPase is not a good target in M. tuberculosis."
He added: "It is becoming
increasingly important to confirm possible targets in drug
discovery. Studies such as this, that provide strong indications
that particular enzymes are not essential, are of great importance
to rationally guide the selection of those targets that are worth
pursuing."
The paper,Two enzymes with redundant fructose bisphosphatase activity sustain
gluconeogenesis and virulence in M. tuberculosis, is
published in Nature Communications.