Meta-Biol

• Pathways

The purinoreceptors are divided into inotropic (P2XR) and metabotropic (P2YR) subtypes whose ligands are the nucleotides ATP and UDP respectively (Cekic et al. 2016). The binding of these nucleotides to their receptors on macrophages have been associated with the activation of the inflammasome leading to the subsequent activation of interleukin 1 beta (IL1β) and TNF-α (Cekic et al. 2016 & Figueiredo et al. 2016). The liberation of ATP comes from tissues facing stressful stimuli such as a tissue injury or microorganism infection, amongst others. As a regulatory mechanism, certain enzymes can reduce ATP to Adenosine and a nucleoside can stimulate signalling pathways leading to the synthesis of anti-inflammatory cytokines (Cekic et al. 2016).

The activation of the receptor P2RX7 was shown to lead to the activation of killing mechanisms or cell death programs, ending up in the elimination of microbes such as Leishmania amazonensis, Mycobacterium tuberculosis, Chlamydia psittaci, and Toxoplasma gondii (Coutinho-Silva et al. 2012 & Idzko, 2014).

Infectious diseases are ones due to the presence of pathogenic microbial agents in human host cells. Processes annotated in this category include bacterial, viral and parasitic infection pathways.

Bacterial infection pathways currently include some metabolic processes mediated by intracellular Mycobacterium tuberculosis, the actions of clostridial, anthrax, and diphtheria toxins, and the entry of Listeria monocytogenes into human cells.

Viral infection pathways currently include the life cycles of SARS-CoV viruses, influenza virus, HIV (human immunodeficiency virus), and human cytomegalovirus (HCMV).

Parasitic infection pathways currently include Leishmania infection-related pathways.

Fungal infection pathways and prion diseases have not been annotated.

Biological processes are captured in Reactome by identifying the molecules (DNA, RNA, protein, small molecules) involved in them and describing the details of their interactions. From this molecular viewpoint, human disease pathways have three mechanistic causes: the inclusion of microbially-expressed proteins, altered functions of human proteins, or changed expression levels of otherwise functionally normal human proteins.

The first group encompasses the infectious diseases such as influenza, tuberculosis and HIV infection. The second group involves human proteins modified either by a mutation or by an abnormal post-translational event that produces an aberrant protein with a novel function. Examples include somatic mutations of EGFR and FGFR (epidermal and fibroblast growth factor receptor) genes, which encode constitutively active receptors that signal even in the absence of their ligands, or the somatic mutation of IDH1 (isocitrate dehydrogenase 1) that leads to an enzyme active on 2-oxoglutarate rather than isocitrate, or the abnormal protein aggregations of amyloidosis which lead to diseases such as Alzheimer's.

Infectious diseases are represented in Reactome as microbial-human protein interactions and the consequent events. The existence of variant proteins and their association with disease-specific biological processes is represented by inclusion of the modified protein in a new or variant reaction, an extension to the 'normal' pathway. Diseases which result from proteins performing their normal functions but at abnormal rates can also be captured, though less directly. Many mutant alleles encode proteins that retain their normal functions but have abnormal stabilities or catalytic efficiencies, leading to normal reactions that proceed to abnormal extents. The phenotypes of such diseases can be revealed when pathway annotations are combined with expression or rate data from other sources.

Depending on the biological pathway/process immediately affected by disease-causing gene variants, non-infectious diseases in Reactome are organized into diseases of signal transduction by growth factore receptors and second messengers, diseases of mitotic cell cycle, diseases of cellular response to stress, diseases of programmed cell death, diseases of DNA repair, disorders of transmembrane transporters, diseases of metabolism, diseases of immune system, diseases of neuronal system, disorders of developmental biology, disorders of extracellular matrix organization, and diseases of hemostatis.