Meta-Biol

• Pathways

Botulinum toxin type A (botA, also known as BoNT/A), a disulfide bonded heavy chain (HC) - light chain (LC) heterodimer ("dichain"), enters the gut typically as a result of consuming contaminated food (Hatheway 1995), as a complex with nontoxic nonhemagglutinin protein (NTNHA, encoded by the C. botulinum ntnha gene) and multiple copies of three hemagglutinin proteins (HA, encoded by the C. botulinum ha17, ha34, and ha70 genes) (Lee et al. 2013). The complex protects the toxin from degradation in the gut and mediates its association with the gut epithelium and transcytosis to enter the circulation. Recent studies in vitro raise the possibility that the toxin may also directly disrupt the basolateral membrane of the gut epithelium (Fujinaga et al. 2013). Circulating toxin molecules associate with gangliosides and synaptic vesicle protein 2 (SV2) exposed by exocytosis at a synapse of a target neuron in the neuromuscular junction (Yowler & Schengrund 2004; Dong et al. 2006). Vesicle recycling brings the toxin into the neuron where the vesicle is acidified (Sudhoff 2004). The lowered pH induces a conformational change in the toxin: its HC forms a passage in the vesicle membrane through which its LC is extruded into the neuronal cytosol and released by reduction of the HC - LC disulfide bond (Montal 2010). The cytosolic LC then catalyzes the cleavage of synaptosomal associated protein 25 (SNAP25) on the cytosolic face of the neuronal plasma membrane (Binz et al. 1994; Schiavo et al. 1993), thereby inhibiting synaptic vesicle fusion with the plasma membrane and exocytosis.

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.