Exam (elaborations)
Exam (elaborations) Advanced structural and functional biochemistry (6101BCBMOL)
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Question 4 of exam. Discussing activation of hypoxia in oxygenated conditions. Question, answer and references.
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Student ID: 8298864. Discuss the immune function relevance of pattern recognition receptors (PRRs) activation of
a hypoxia pathway despite the presence of oxygen.
Pattern recognition receptors (PPR) are proteins able to detect molecules frequently found on
pathogens, these include PAMPS (pathogen associated molecular patterns) and DAMPS (damage
associated molecular patterns). PAMPs that have been identified so far are proteins such as bacterial
flagellin, nucleic acids such as viral ssRNA or glycans such as bacterial lipopolysaccharide (LPS). PPRs
are most seen on antigen presenting immune cells such as dendritic cells and macrophages.
Although they can be found on other immune and non-immune cells. They are part of the innate
immune system. There are four types of PPR. Toll-like receptors (TLR) are single-pass membrane
spanning proteins that recognise structurally conserved molecules originated from microbes.
Nucleotide-binding oligomerization domain-like receptors (NLR) are intracellular sensors of PAMPS
that have entered the cell via phagocytosis or pores, and DAMPS associated with cellular stress. C-
type lectin receptors (CLR) play an important role in the recognition and induction of the adaptive
immune system. CLRs can efficiently interact with viruses however some viruses such as HIV can
avoid CLRs and are able to promote infection. (Bermejo-Jambrina, M., et al, 2018). RIG-1 like
receptors (RLR) (retinoic acid-inducible gene-I-like receptors) are a family of “DExD/H box RNA
helicases” (Loo, Y. M., & Gale, M., 2011) that act as intracellular sensors for viral infection by
detecting PAMPs, this triggers innate immunity and inflammation.
Mammalian TLRs represent a family of about 12 membrane proteins that trigger innate immune
responses through nuclear factor-κB (NF-κB)-dependent and interferon (IFN)-regulatory factor-
dependent signalling pathways. It is thought they have a regulatory role in inflammation in
infectious and non-infectious diseases. Inflammation or infection is commonly characterised by
dramatic shifts in a tissue’s metabolic activity. This can lead to increased activity and therefore
consumption of O2 within immune cells, and a possible constriction of oxygen supply due to
thrombosis or inflammation of the vascular support system.
The oxygen sensing pathway can become activated during infection or inflammation, triggering the
Hypoxia-inducible factor (HIF). HIF is a heterodimer consisting of two subunits: HIF-1α and HIF-1β.
HIF-1α is induced in hypoxic conditions whereas HIF-1β is constitutively expressed. HIF facilitates
both oxygen delivery and adaptation to oxygen deprivation through the stimulation of gene
expression. Under normoxic conditions, HIF-1α undergoes proline hydroxylation catalysed by prolyl-
4-hydroxylases (PHDs) at the oxygen-dependent degradation domain on the c-terminus. Von Hipple-
Lindau (VHL) can specifically recognize the hydroxylated form of HIF-1α. However, this does not
occur under hypoxic conditions. Under hypoxic conditions HIF-1α is exempt from VHL degradation
and the stable heterodimer binds to hypoxia response elements within promoter regions to switch
on transcription of target genes such as VEGF. With vascular perfusion restored the oxygen tension
rises and restores to the normal levels. Oxygen binds to HIf-1α and inhibits the transcription of VEGF.
Warnecke, C., et al (2003) investigated how HIF could be utilised for patients with ischemic disease,
they wanted to activate HIF in higher oxygen levels to ensure its use as a therapeutic. Warnecke and
colleagues tested three known prolyl 4‐hydroxylase inhibitors—l‐Mim, 3,4‐DHB, and S956711, all
three compounds activated HIF, although with different potencies, and induced HIF target genes in
mammalian cells. This means HIF can be activated in the presence of oxygen and be exploited as a
therapeutic.
Most immune responses to PPR activation would rely on hypoxic or extremely low oxygen conditions
to initiate the hypoxia pathway. However, in instances such as cancer there may be a fundamental
cellular change to a hypoxic environment in the presence of oxygen to perform the cells required
function. For example, the Warburg effect discusses how even in aerobic conditions the cells
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