Pathways

TTP

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.

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 biosynthesis of L-tryptophan begins with L-glutamine interacting with a chorismate through a anthranilate synthase which results in a L-glutamic acid, a pyruvic acid, a hydrogen ion and a 2-aminobenzoic acid. The aminobenzoic acid interacts with a phosphoribosyl pyrophosphate through an anthranilate synthase component II resulting in a pyrophosphate and a N-(5-phosphoribosyl)-anthranilate. The latter compound is then metabolized by an indole-3-glycerol phosphate synthase / phosphoribosylanthranilate isomerase resulting in a 1-(o-carboxyphenylamino)-1-deoxyribulose 5'-phosphate. This compound then interacts with a hydrogen ion through a indole-3-glycerol phosphate synthase / phosphoribosylanthranilate isomerase resulting in the release of carbon dioxide, a water molecule and a (1S,2R)-1-C-(indol-3-yl)glycerol 3-phosphate. The latter compound then interacts with a D-glyceraldehyde 3-phosphate and an Indole. The indole interacts with an L-serine through a tryptophan synthase, β subunit dimer resulting in a water molecule and an L-tryptophan. The metabolism of L-tryptophan starts with L-tryptophan being dehydrogenated by a tryptophanase / L-cysteine desulfhydrase resulting in the release of a hydrogen ion, an Indole and a 2-aminoacrylic acid. The latter compound is isomerized into a 2-iminopropanoate. This compound then interacts with a water molecule and a hydrogen ion spontaneously resulting in the release of an Ammonium and a pyruvic acid. The pyruvic acid then interacts with a coenzyme A through a NAD driven pyruvate dehydrogenase complex resulting in the release of a NADH, a carbon dioxide and an Acetyl-CoA

This pathway depicts the metabolic reactions and pathways associated with tryptophan metabolism in animals. Tryptophan is an essential amino acid. This means that it cannot be synthesized by humans and other mammals and therefore must be part of the diet. Unlike animals, plants and microbes can synthesize tryptophan from shikimic acid or anthranilate. As one of the 20 proteogenic amino acids, tryptophan plays an important role in protein biosynthesis through the action of tryptophanyl-tRNA synthetase. As shown in this pathway, tryptophan can be linked to the tryptophanyl-tRNA via either the mitochondrial or cytoplasmic tryptophan tRNA ligases. Also shown in this pathway map is the conversion of tryptophan to serotonin (a neurotransmitter). In this process, tryptophan is acted upon by the enzyme tryptophan hydroxylase, which produces 5-hydroxytryptophan (5HTP). 5HTP is then converted into serotonin (5-HT) via aromatic amino acid decarboxylase. Serotonin, in turn, can be converted into N-acetyl serotonin (via serotonin-N-acetyltransferase) and then melatonin (a neurohormone), via 5-hydroxyindole-O-methyltransferase. The melatonin can be converted into 6-hydroxymelatonin via the action of cytochrome P450s in the endoplasmic reticulum. Serotonin has other fates as well. As depicted in this pathway it can be converted into N-methylserotonin via Indolethylamine-N-methyltransferase (INMT) or it can be converted into formyl-5-hydroxykynurenamine via indoleamine 2,3-dioxygenase. Serotonin may also be converted into 5-methoxyindoleacetate via a series of intermediates including 5-hydroxyindoleacetaldehyde and 5-hydroxyindoleacetic acid. Tryptophan can be converted or broken down into many other compounds as well. It can be converted into tryptamine via the action of aromatic amino acid decarboxylase. The resulting tryptamine can then be converted into indoleacetaldehyde via kynurenine 3-monooxygenase and then into indoleacetic acid via the action of aldehyde dehydrogenase. Tryptophan also leads to the production of a very important compound known as kynurenine. Kynurenine is synthesized via the action of tryptophan 2,3-dioxygnase, which produces N-formylkynurenine. This compound is converted into kynurenine via the enzyme known as kynurenine formamidase (AFMID). Kynurenine has at least 3 fates. First, kynurenine can undergo deamination in a standard transamination reaction yielding kynurenic acid. Secondly, kynurenine can undergo a series of catabolic reactions (involving kynureninase and kynurenine 3-monooxygenase) producing 3-hydroxyanthranilate plus alanine. In this reaction, kynureninase catabolizes the conversion of kynurenine into anthranilic acid while kynurenine—oxoglutarate transaminase (also known as kynurenine aminotransferase or glutamine transaminase K, GTK) catabolizes its conversion into kynurenic acid. The action of kynurenine 3-hydroxylase on kynurenic acid leads to 3-hydroxykynurenine. The oxidation of 3-hydroxyanthranilate converts it into 2-amino-3-carboxymuconic 6-semialdehyde, which has two fates. It can either degrade to form acetoacetate or it can cyclize to form quinolate. Most of the body’s 3-hydroxyanthranilate leads to the production of acetoacetate (a ketone body), which is why tryptophan is also known as a ketogenic amino acid. An important side reaction in the liver involves a non-enzymatic cyclization into quinolate followed by transamination and several rearrangements to yield limited amounts of nicotinic acid, which leads to the production of a small amount of NAD+ and NADP+.

This pathway depicts the metabolic reactions and pathways associated with tryptophan metabolism in animals. Tryptophan is an essential amino acid. This means that it cannot be synthesized by humans and other mammals and therefore must be part of the diet. Unlike animals, plants and microbes can synthesize tryptophan from shikimic acid or anthranilate. As one of the 20 proteogenic amino acids, tryptophan plays an important role in protein biosynthesis through the action of tryptophanyl-tRNA synthetase. As shown in this pathway, tryptophan can be linked to the tryptophanyl-tRNA via either the mitochondrial or cytoplasmic tryptophan tRNA ligases. Also shown in this pathway map is the conversion of tryptophan to serotonin (a neurotransmitter). In this process, tryptophan is acted upon by the enzyme tryptophan hydroxylase, which produces 5-hydroxytryptophan (5HTP). 5HTP is then converted into serotonin (5-HT) via aromatic amino acid decarboxylase. Serotonin, in turn, can be converted into N-acetyl serotonin (via serotonin-N-acetyltransferase) and then melatonin (a neurohormone), via 5-hydroxyindole-O-methyltransferase. The melatonin can be converted into 6-hydroxymelatonin via the action of cytochrome P450s in the endoplasmic reticulum. Serotonin has other fates as well. As depicted in this pathway it can be converted into N-methylserotonin via Indolethylamine-N-methyltransferase (INMT) or it can be converted into formyl-5-hydroxykynurenamine via indoleamine 2,3-dioxygenase. Serotonin may also be converted into 5-methoxyindoleacetate via a series of intermediates including 5-hydroxyindoleacetaldehyde and 5-hydroxyindoleacetic acid. Tryptophan can be converted or broken down into many other compounds as well. It can be converted into tryptamine via the action of aromatic amino acid decarboxylase. The resulting tryptamine can then be converted into indoleacetaldehyde via kynurenine 3-monooxygenase and then into indoleacetic acid via the action of aldehyde dehydrogenase. Tryptophan also leads to the production of a very important compound known as kynurenine. Kynurenine is synthesized via the action of tryptophan 2,3-dioxygnase, which produces N-formylkynurenine. This compound is converted into kynurenine via the enzyme known as kynurenine formamidase (AFMID). Kynurenine has at least 3 fates. First, kynurenine can undergo deamination in a standard transamination reaction yielding kynurenic acid. Secondly, kynurenine can undergo a series of catabolic reactions (involving kynureninase and kynurenine 3-monooxygenase) producing 3-hydroxyanthranilate plus alanine. In this reaction, kynureninase catabolizes the conversion of kynurenine into anthranilic acid while kynurenine—oxoglutarate transaminase (also known as kynurenine aminotransferase or glutamine transaminase K, GTK) catabolizes its conversion into kynurenic acid. The action of kynurenine 3-hydroxylase on kynurenic acid leads to 3-hydroxykynurenine. The oxidation of 3-hydroxyanthranilate converts it into 2-amino-3-carboxymuconic 6-semialdehyde, which has two fates. It can either degrade to form acetoacetate or it can cyclize to form quinolate. Most of the body’s 3-hydroxyanthranilate leads to the production of acetoacetate (a ketone body), which is why tryptophan is also known as a ketogenic amino acid. An important side reaction in the liver involves a non-enzymatic cyclization into quinolate followed by transamination and several rearrangements to yield limited amounts of nicotinic acid, which leads to the production of a small amount of NAD+ and NADP+.

The tryptophan biosynthesis begins with chorismate interacting with a L-glutamine through a Anthranilate synthase resulting in the release of glutamic acid, pyruvic acid, hydrogen ion and 2-aminobenzoic acid. The latter compound reacts with a PRPP through an Anthranilate phosphoribosyltransferase resulting in the release of pyrophosphate and a N-5-phosphoribosyl anthranilate. The latter compound is isomerized through a N-5 phosphoribosylanthranilate isomerase resulting in the release of a 1-(2-carboxyphenylamino)-1-deoxy-D-ribulose 5-phosphate which then reacts with a hydrogen ion resulting in the release of water, carbon dioxide and indoleglycerol phosphate. The latter compound reacts with a tryptophan synthase resulting in the release of D-glyceraldehyde 3-phosphate and Indole. Indole reacts with L-serine through a tryptophan synthase resulting in the release of water and tryptophan. The degradation of tryptophan can occur in 2 ways: a) tryptophan reacting with an aromatic aminotransferase resulting in the release of indole 3 pyruvate which can then be transformed into indoleacetaldehyde through a pyruvate isozyme. Indoleacetaldehyde reacts with alcohol dehydrogenase resulting in a tryptophol B) tryptophan is consumed through the nicotinate biosynthesis