Pathways

Isovalerylglycine (IVG) is an acyl glycine. Acyl glycines are normally minor metabolites of fatty acids. However, the excretion of certain acyl glycines is increased in several inborn errors of metabolism. In certain cases the measurement of these metabolites in body fluids can be used to diagnose disorders associated with mitochondrial fatty acid beta-oxidation. Acyl glycines are produced through the action of glycine N-acyltransferase (EC 2.3.1.13) which is an enzyme that catalyzes the chemical reaction: acyl-CoA + glycine < -- > CoA + N-acylglycine. Isovalerylglycine is a byproduct of the catabolism of the aminoacid leucine. Accumulation of isovalerylglycine occurs in Isovaleric Acidemia (IVA). IVA (OMIM/ McKusick 243500) is an autosomal recessive disorder caused by mutations in the isovaleryl-CoA dehydrogenase (EC 1.3.99.10) gene. The deficiency of this enzyme in the metabolism of leucine leads to the accumulation of a series of isovaleryl-CoA metabolites, such as isovalerylglycine. It is very important to caution for false positive results when screening for isovaleric acidemia by tandem mass spectrometry based on dried blood-spot levels of C5-acylcarnitines, including isovalerylcarnitine and its isomer, pivaloylcarnitine; pivaloylcarnitine is derived from pivalate-generating antibiotics, and has caused many false-positive results. Isovalerylglycine is a biomarker for the consumption of cheese.

Kynurenic acid is an indole uremic toxin compound that is formed through metabolism from dietary tryptophan in liver hepatic cells. After being transported into a hepatocyte from portal circulation tryptophan undergoes a reaction with the enzyme tryptophan-2,3-dioxygenase to initially form kynurenine and then with a kynurenine aminotransferase enzyme to ultimately form kynurenic acid. When this compound enters into systemic circulation it is shown to be a major uremic toxin through high levels of retention. Kynurenic acid is shown to activate aryl hydrocarbon receptors that can lead to renal impairment, and it also disrupts the electron transport chain and oxidative phosphorylation causing muscle atrophy.

Kynurenine is a uremic toxin that is produced when a person has uremia or renal failure. Kynurenine is naturally synthesized in the body from tryptophan. Tryptophan is consumed through foods such as milk, eggs, chicken, turkey, and oats. Tryptophan is then transported from the small intestine into the blood by an amino acid transport. In the blood it travels to the liver and is transported into a hepatocyte by an amino acid transporter. The kynurenine pathway becomes dysregulated, potentially through over-stimulation by interferon gamma (IFNG). This hyperstimulation leads to large reductions in tryptophan levels as the indole dioxygenase (IDO) enzyme becomes more active. IDO activation results in the generation (from tryptophan) of large amounts of kynurenine (and its other metabolites) through a self-stimulating autocrine process. Kynurenine binds to the arylhydrocarbon receptor (AhR) found in most immune cells [5-7]. In addition to increased kynurenine production via IDO mediated synthesis, hyopalbuminemia can also lead to the release of bound kynurenine (and other immunosuppressive LysoPCs) into the bloodstream to fuel this kynurenine-mediated process. Regardless of the source of kynurenine, the kynurenine-bound AhR will migrate to the nucleus to bind to NF-kB which leads to more production of the IDO enzyme, which leads to more production of kynureneine and more loss of tryptophan. Kynurenine then enters the blood via a liver organic anion transporter such as solute carrier family 22 member 9. Kynurenine is shown to activate aryl hydrocarbon receptors that can lead to renal impairment, apoptosis, and kynurenine has also been found to disrupt the electron transport chain and oxidative phosphorylation causing muscle atrophy.

N-Acetyl-1-methylhistidine belongs to the class of organic compounds known as histidine and derivatives. Histidine and derivatives are compounds containing histidine or a derivative thereof resulting from a reaction of histidine at the amino group or the carboxy group, or from the replacement of any hydrogen of glycine by a heteroatom. N-Acetyl-1-methylhistidine is an acetylated derivative of 1-methylhistidine and a very strong basic compound (based on its pKa). It has been found to be associated with chronic kidney disease: the higher the N-acetyl-1-methylhistidine levels, the lower the estimated glomerular filtration rate. This could make N-acetyl-1-methylhistidine a biomarker for chronic kidney disease. Higher circulating levels of five of these N-acetylated amino acids, namely, N-δ-acetylornithine, N-acetyl-1-methylhistidine, N-acetyl-3-methylhistidine, N-acetylhistidine, and N2,N5-diacetylornithine, were associated with kidney failure. The NAT8 gene has been associated with 14 N-acetylated amino acids, including N-Acetyl-3-methylhistidine.

N-Acetyl-3-methylhistidine, an N-acetyl-L-amino acid, belongs to the class of organic compounds known as histidine and derivatives. Histidine and derivatives are compounds containing histidine or a derivative thereof resulting from a reaction of histidine at the amino group or the carboxy group, or from the replacement of any hydrogen of glycine by a heteroatom. N-Acetyl-3-methylhistidine is an acetylated derivative of 3-methylhistidine and a very strong basic compound (based on its pKa). N-Acetyl-3-methylhistidine has been found to be associated with prostate cancer. Higher circulating levels of five of these N-acetylated amino acids, namely, N-δ-acetylornithine, N-acetyl-1-methylhistidine, N-acetyl-3-methylhistidine, N-acetylhistidine, and N2,N5-diacetylornithine, were associated with kidney failure. The NAT8 gene has been associated with 14 N-acetylated amino acids, including N-Acetyl-3-methylhistidine.

N-Acetyl-L-alanine or N-Acetylalanine, belongs to the class of organic compounds known as N-acyl-alpha amino acids. N-acyl-alpha amino acids are compounds containing an alpha amino acid which bears an acyl group at its terminal nitrogen atom. N-Acetyl-L-alanine can also be classified as an alpha amino acid or a derivatized alpha amino acid. Technically, N-alpha-Acetyl-L-alanine is a biologically available N-terminal capped form of the proteinogenic alpha amino acid L-alanine. N-acetyl amino acids can be produced either via direct synthesis of specific N-acetyltransferases or via the proteolytic degradation of N-acetylated proteins by specific hydrolases. N-terminal acetylation of proteins is a widespread and highly conserved process in eukaryotes that is involved in protection and stability of proteins. N-Acetyl-L-alanine is a product of the enzyme known as ribosomal alanine N-acetyltransferase (EC 2.3.1.128) which catalyzes the transfer of the acetyl group of acetyl CoA to proteins bearing an N-terminal alanine. Excessive amounts N-acetyl amino acids can be detected in the urine with individuals with aminoacylase I deficiency, a genetic disorder. Individuals with aminoacylase I deficiency will experience convulsions, hearing loss and difficulty feeding. Many N-acetylamino acids, including N-acetylalanine, are classified as uremic toxins. Uremic toxins are a diverse group of endogenously produced molecules that, if not properly cleared or eliminated by the kidneys, can cause kidney damage, cardiovascular disease and neurological deficits.

N-Acetyl-L-histidine or N-Acetylhistidine, belongs to the class of organic compounds known as N-acyl-alpha amino acids. N-acyl-alpha amino acids are compounds containing an alpha amino acid which bears an acyl group at its terminal nitrogen atom. N-Acetylhistidine can also be classified as an alpha amino acid or a derivatized alpha amino acid. Technically, N-Acetylhistidine is a biologically available N-terminal capped form of the proteinogenic alpha amino acid L-histidine. N-acetyl amino acids can be produced either via direct synthesis of specific N-acetyltransferases or via the proteolytic degradation of N-acetylated proteins by specific hydrolases. N-terminal acetylation of proteins is a widespread and highly conserved process in eukaryotes that is involved in protection and stability of proteins. Several proteins from prokaryotes and archaea are also modified by N-terminal acetylation. The majority of eukaryotic N-terminal-acetylation reactions occur through N-acetyltransferase enzymes or NAT. The substrate specificities of different NAT enzymes are mainly determined by the identities of the first two N-terminal residues of the target protein. The human NatA complex co-translationally acetylates N-termini that bear a small amino acid (A, S, T, C, and occasionally V and G). N-acetylated amino acids, such as N-acetylhistidine can be released by an N-acylpeptide hydrolase from peptides generated by proteolytic degradation. In addition to the NAT enzymes and protein-based acetylation, N-acetylation of free histidine can also occur. In particular, N-Acetylhistidine can be biosynthesized from L-histidine and acetyl-CoA by the enzyme histidine N-acetyltransferase (EC 2.3.1.33). Many N-acetylamino acids are classified as uremic toxins if present in high abundance in the serum or plasma. Uremic toxins are a diverse group of endogenously produced molecules that, if not properly cleared or eliminated by the kidneys, can cause kidney damage, cardiovascular disease and neurological deficits. In scientific studies, N-Acetyl-L-histidine has been examined for its potential neuroprotective effects in conditions such as age-related macular degeneration (AMD), retinitis pigmentosa, and glaucoma. It has also been investigated for its role in supporting retinal function and visual health. Additionally, it may modulate cellular signaling pathways involved in inflammation and cell survival.

N-Acetyl-L-methionine or N-Acetylmethionine, belongs to the class of organic compounds known as N-acyl-alpha amino acids. N-acyl-alpha amino acids are compounds containing an alpha amino acid which bears an acyl group at its terminal nitrogen atom. N-Acetylmethionine can also be classified as an alpha amino acid or a derivatized alpha amino acid. Technically, N-Acetylmethionine is a biologically available N-terminal capped form of the proteinogenic alpha amino acid L-methionine. N-acetyl amino acids can be produced either via direct synthesis of specific N-acetyltransferases or via the proteolytic degradation of N-acetylated proteins by specific hydrolases. N-terminal acetylation of proteins is a widespread and highly conserved process in eukaryotes that is involved in protection and stability of proteins. About 85% of all human proteins and 68% of all yeast proteins are acetylated at their N-terminus. The majority of eukaryotic N-terminal-acetylation reactions occur through N-acetyltransferase enzymes or NAT. he substrate specificities of different NAT enzymes are mainly determined by the identities of the first two N-terminal residues of the target protein. The human NatA complex co-translationally acetylates N-termini that bear a small amino acid (A, S, T, C, and occasionally V and G). NatA also exists in a monomeric state and can post-translationally acetylate acidic N-termini residues (D-, E-). NatB and NatC acetylate N-terminal methionine with further specificity determined by the identity of the second amino acid. N-acetylated amino acids, such as N-acetylmethionine can be released by an N-acylpeptide hydrolase from peptides generated by proteolytic degradation. In addition to the NAT enzymes and protein-based acetylation, N-acetylation of free methionine can also occur. In particular, N-Acetylmethionine can be biosynthesized from L-methionine and acetyl-CoA by the enzyme methionine N-acetyltransferase. Many N-acetylamino acids, including N-acetylmethionine are classified as uremic toxins if present in high abundance in the serum or plasma. Uremic toxins are a diverse group of endogenously produced molecules that, if not properly cleared or eliminated by the kidneys, can cause kidney damage, cardiovascular disease and neurological deficits.

N-Acetyl-L-phenylalanine or N-Acetylphenylalanine, belongs to the class of organic compounds known as N-acyl-alpha amino acids. N-acyl-alpha amino acids are compounds containing an alpha amino acid which bears an acyl group at its terminal nitrogen atom. N-Acetyl-L-phenylalanine can also be classified as an alpha amino acid or a derivatized alpha amino acid. Technically, N-Acetyl-L-phenylalanine is a biologically available N-terminal capped form of the proteinogenic alpha amino acid L-phenylalanine. N-acetyl amino acids can be produced either via direct synthesis of specific N-acetyltransferases or via the proteolytic degradation of N-acetylated proteins by specific hydrolases. N-terminal acetylation of proteins is a widespread and highly conserved process in eukaryotes that is involved in protection and stability of proteins. About 85% of all human proteins and 68% of all yeast proteins are acetylated at their N-terminus. Several proteins from prokaryotes and archaea are also modified by N-terminal acetylation. The majority of eukaryotic N-terminal-acetylation reactions occur through N-acetyltransferase enzymes or NAT. These enzymes consist of three main oligomeric complexes NatA, NatB, and NatC, which are composed of at least a unique catalytic subunit and one unique ribosomal anchor. The substrate specificities of different NAT enzymes are mainly determined by the identities of the first two N-terminal residues of the target protein. The human NatA complex co-translationally acetylates N-termini that bear a small amino acid (A, S, T, C, and occasionally V and G). In addition to the NAT enzymes and protein-based acetylation, N-acetylation of free phenylalanine can also occur. In particular, N-Acetyl-L-phenylalanine can be biosynthesized from L-phenylalanine and acetyl-CoA by the enzyme phenylalanine N-acetyltransferase. N-Acetyl-L-phenylalanine is a potential uremic toxin and is considered as a hazardous amphipathic metabolite of phenylalanine. Many N-acetylamino acids, including N-acetylphenylalanine, are classified as uremic toxins. Uremic toxins are a diverse group of endogenously produced molecules that, if not properly cleared or eliminated by the kidneys, can cause kidney damage, cardiovascular disease and neurological deficits. N-Acetyl-L-phenylalanine appears in large amount in urine of patients with phenylketonuria (PKU), which is a human genetic disorder due to the lack of phenylalanine hydroxylase, the enzyme necessary to metabolize phenylalanine to tyrosine. N-Acetyl-L-phenylalanine is a product of enzyme phenylalanine N-acetyltransferase [EC 2.3.1.53] which is found in the phenylalanine metabolism pathway. N-Acetyl-L-phenylalanine is produced for medical, feed, and nutritional applications such as in the preparation of aspartame. Afalanine (N-Acetyl-DL-phenylalanine) is also approved for use as an antidepressant.

N-Acetyl-L-proline or N-Acetylproline, belongs to the class of organic compounds known as N-acyl-alpha amino acids. N-acyl-alpha amino acids are compounds containing an alpha amino acid which bears an acyl group at its terminal nitrogen atom. N-Acetylproline can also be classified as an alpha amino acid or a derivatized alpha amino acid. Technically, N-Acetylproline is a biologically available N-terminal capped form of the proteinogenic alpha amino acid L-proline. N-acetyl amino acids can be produced either via direct synthesis of specific N-acetyltransferases or via the proteolytic degradation of N-acetylated proteins by specific hydrolases. N-terminal acetylation of proteins is a widespread and highly conserved process in eukaryotes that is involved in protection and stability of proteins. About 85% of all human proteins and 68% of all yeast proteins are acetylated at their N-terminus. The majority of eukaryotic N-terminal-acetylation reactions occur through N-acetyltransferase enzymes or NATs. In addition to the NAT enzymes and protein-based acetylation, N-acetylation of free proline can also occur. Many N-acetylamino acids, including N-acetylproline are classified as uremic toxins if present in high abundance in the serum or plasma. N-acetylproline in the body can cause kidney damage and contribute to tumorigenesis, L-proline can be obtained from the diet from foods that are high in protein such as meat, fish, and dairy. Once ingested, L-proline gets converted to N-acetylproline in the liver via NATs.