Pathways

The trp operon in E. coli contains five genes that produce proteins that are used in the production of the amino acid tryptophan when needed by the cell. When tryptophan levels in the cell are high, tryptophan binds to the trp operon repressor protein, which activates it. The activated repressor then binds to the operator, preventing RNA polymerase from binding and transcribing the operon. However, when tryptophan concentrations in the cell are low, it doesn't bind to the repressor, preventing it from binding to the operator, and allowing transcription until the terminator after the trpA gene is reached. The trp operon is also regulated by the amount of useable trp tRNA present. Upon start of transcription, the leader peptide, encoded by the trpL gene, will begin to be transcribed. Because this peptide contains two trp residues next to each other, and trp is a relatively uncommon amino acid, if there is a low concentration of trp tRNA in the cell, it can cause the leader peptide to stall during transcription. This allows for the section of mRNA immediately after the stalled ribosome to form the anti-termination hairpin. This hairpin prevents the formation of the terminal hairpin that contains a termination sequence that would stop transcription after the leader peptide. Because the anti-termination hairpin is allowed to form, transcription of the rest of the operon can continue. However, when the cell contains a high concentration of trp tRNA, the transcription does not stall, which allows for the formation of the transcription terminator to form before the rest of the genes in the operon, preveinting their transcription. The trpE and trpD genes encode for anthranilate synthase components 1 and 2 respectively. These combine to create anthranilate synthase, which produces anthranilate and pyruvate from chorismate. The trpC gene encodes the tryptophan biosynthesis protein that takes the anthranilate from the previous protein and converts it in two steps to indole-3-glycerol. Finally, the trpB and trpA genes encode for tryptophan beta and alpha subunits respectively. Two of each subunit come together to form tryptophan synthase. This protein then takes the previous compound, as well as a molecule of L-serine, and catalzes their conversion into tryptophan, as well as water and D-glyceraldehyde-3-phosphate.

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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+

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+

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+.