Pathways

Generally KP is a major degradative pathway that occurs in the liver, which synthesizes NAD+ from tryptophan (TRP). TRP acts as a precursor, in the central nervous system to several metabolic pathways, such as synthesis of kynurenine (KYN), serotonin, melatonin (Ruddick et al., 2006). The rate-limiting step in KP is the indole ring opening which is catalysed either by indoleamine-2,3-dioxygenases (IDO-1) or tryptophan 2,3-dioxygenase (TDO). The expression of IDO-1 and TDO is observed in different tissues and they are exposed to different stimuli, proposing that they have distinct functions in health and disease. The enzymes of KP are produced in many cell types and tissues which were significantly seen with the abundance of subsequent metabolites such as NAD+ and its reduced forms NADH (reduced nicotinamide adenine dinucleotide (phosphate)), pellagra-preventing factor, niacin or vitamin B3, PA (picolinic acid), NMDA (N-methyl-D-aspartate) receptor agonist QUIN (quinolinic acid) and antagonist KYNA (kynurenic acid), 3-HK (3-hydroxykynurenine) and 3-HAA (3-hydroxyanthranilic acid) (Badawy., 2017). TRP is converted to N′-formylkynurenine (NFK) either by TDO in liver or by IDO-1 extrahepatically. KYN is synthesized from NFK by the enzyme NFK formamidase (FAM). In the pathway, catalytic activity showing hydroxylation of KYN to 3-HK by KYN hydroxylase (KMO) followed by 3-HK hydrolysis to 3-HAA by kynureninase is noted. Kynureninase can also hydrolyze KYN to anthranilic acid (AA) while kynurenine aminotransferases (I, II, III) (KATs) desaminate KYN to KYNA (Sas et al., 2018). In the main catabolic pathway, along with 3-HAA, 2-amino-3-carboxymuconoate semialdehyde is produced. This semialdehyde latter process to form QUIN or decarboxylated to PA. QUIN is further metabolised by quinolinic acid phosphoribosyl transferase (QPRT) to niacin and consequently to NAD+

The members of the large family of matricellular proteins including thrombospondin-1 (TSP1) play important roles in genesis and remodeling of multiple tissues including cartilage and vasculature. TSP1 is one of the important pivots that regulate vascular tissue homeostasis whereas its key function is the negative control of angiogenesis. TSP1 was the first naturally occurring protein inhibitor of angiogenesis to be identified; its anti-angiogenic effects have since been established in a multitude of experimental models and linked to specific epitopes in the multi-domain, multi-functional TSP1 molecule. TSP1 is the first identified, and therefore best studied thrombospondin family representative, its structure is thus considered as prototype for the other family members. In the thrombospondin family, another member, TSP2 has a similar domain structure and, non-surprisingly, its functions significantly overlap with those of TSP1. Specifically, both TSP1 and TSP2 potently inhibit angiogenesis.

TTP

TTP

Tucatinib is a drug that is not metabolized by the human body as determined by current research and biotransformer analysis. Tucatinib passes through the liver and is then excreted from the body mainly through the kidney.