Pyridoxamine
Encyclopedia
Pyridoxamine is a vitamer
in the vitamin B6
family, which includes pyridoxal
and pyridoxine
. Pyridoxamine is converted to the biologically active form of vitamin B6, pyridoxal 5-phosphate, via the vitamin B6 salvage pathway. Vitamin B6 acts as an enzyme cofactor in a variety of metabolic processes. In food, pyridoxamine is commonly found as a 5’-phosphate derivative, which is hydrolyzed by intestinal phosphatase
s to pyridoxamine and absorbed in the jejunum
. Absorbed pyridoxamine is converted to pyridoxamine 5’-phosphate by pyridoxal kinase
, which is further converted to the active pyridoxal 5-phosphate by pyridoxamine-phosphate transaminase
or pyridoxine 5’-phosphate oxidase
.
Pyridoxamine is based on a pyridine
ring structure, with hydroxyl
, methyl, aminomethyl, and hydroxymethyl
substituent
s. It differs from pyridoxine by the substituent at the 4-position. The phenol at position 3 and aminomethyl group at position 4 of its ring endow pyridoxamine with a variety of chemical properties, including the scavenging
of free radical species and carbonyl species formed in sugar and lipid degradation and chelation
of metal ions that catalyze Amadori reactions
.
2+ and Fe
3+. The 3'-hydroxyl group of pyridoxamine allows for efficient hydroxyl radical
scavenging.
Pyridoxamine inhibits the Maillard reaction
and can block the formation of advanced glycation endproducts, which are associated with medical complications of diabetes. Pyridoxamine is hypothesized to trap intermediates in the formation of Amadori products released from glycated
protein
s, possibly preventing the breakdown of glycated proteins by disrupting the catalysis
of this process through disruptive interactions with the metal ions crucial to the redox reaction. One research study found that pyridoxamine specifically reacts with the carbonyl
group in Amadori products, but inhibition of post-Amadori reactions (that can lead to advanced glycation endproducts) is due in much greater part to the metal chelation
effects of pyridoxamine.
A variety of preclinical studies in animal model
s of diabetes indicated that pyridoxamine improved kidney
histology
comparable or superior to aminoguanidine. Because of these results, pyridoxamine has been investigated for clinical utility in the treatment of diabetic nephropathy
.
Pyridoxamine also inhibits the formation of advanced lipoxidation endproducts during lipid peroxidation
reactions by reaction with dicarbonyl
intermediates. In other preclinical research, pyridoxamine may be efficacious in treating diabetic neuropathy
and retinopathy
associated with diabetes and kidney stone
disease. In one study, pyridoxamine was more effective at protecting from ionizing radiation
-induced gastrointestinal epithelial apoptosis
than amifostine
(the only radioprotector currently Food and Drug Administration
(FDA)-approved) due to pyridoxamine reactive oxygen species and reactive carbonyl species scavanging profile.
, often as the hydrochloride
salt, pyridoxamine dihydrochloride. However, in the United States
, the FDA ruled in January 2009 that pyridoxamine must be regulated as a pharmaceutical drug because it is the active ingredient in Pyridorin, a drug designed by Biostratum, Inc., to prevent the progression of diabetic nephropathy
.
A patent
for Pyridorin, from an application by Biostratum, was published in 2004. Pyridorin had success in early clinical trials, found to be effective in slowing the progression of diabetic neuropathy in a phase II trial on 224 patients. However, the clinical trial progression of Pyridorin was stalled when it was determined that the active ingredient (pyridoxamine) was commonly available for purchase on the Internet
. As the subject of an Investigational New Drug Application with the FDA, Biostratum submitted a Citizen Petition to the FDA on July 29, 2005, seeking to disallow sales of pyridoxamine-containing supplements. This petition was opposed by the Council for Responsible Nutrition, a trade association
of the dietary supplement industry. On January 12, 2009, the FDA ruled that products containing pyridoxamine are excluded from the definition of dietary supplements as defined by the Dietary Supplement Health and Education Act of 1994. The FDA stated that the status of Pyridorin as an investigational new drug, as a result of an application filed by BioStratum in July 1999 and effective on September 1, 1999, meant that "the marketing of pyridoxamine in a dietary supplement is essentially equivalent to the marketing of an investigational new drug as a dietary supplement" because there was an "absence of independent, verifiable evidence that the substance was marketed as a food or a dietary supplement prior to its authorization for investigation as a new drug."
Vitamer
A vitamer of a particular vitamin is any of a number of chemical substances, each of which shows vitamin activity. Very commonly each "vitamin" is not a single chemical, but rather multiple chemical substances called vitamers, each of which is defined by its different biological activity.For...
in the vitamin B6
Vitamin B6
Vitamin B6 is a water-soluble vitamin and is part of the vitamin B complex group. Several forms of the vitamin are known, but pyridoxal phosphate is the active form and is a cofactor in many reactions of amino acid metabolism, including transamination, deamination, and decarboxylation...
family, which includes pyridoxal
Pyridoxal
Pyridoxal is one of the three natural forms of vitamin B6, along with pyridoxamine and pyridoxine . All of these forms are converted in the human body into a single biologically active form, pyridoxal 5-phosphate. All three forms of vitamin B6 are heterocyclic organic compounds...
and pyridoxine
Pyridoxine
Pyridoxine is one of the compounds that can be called vitamin B6, along with pyridoxal and pyridoxamine. It differs from pyridoxamine by the substituent at the '4' position. It is often used as 'pyridoxine hydrochloride'.-Chemistry:...
. Pyridoxamine is converted to the biologically active form of vitamin B6, pyridoxal 5-phosphate, via the vitamin B6 salvage pathway. Vitamin B6 acts as an enzyme cofactor in a variety of metabolic processes. In food, pyridoxamine is commonly found as a 5’-phosphate derivative, which is hydrolyzed by intestinal phosphatase
Phosphatase
A phosphatase is an enzyme that removes a phosphate group from its substrate by hydrolysing phosphoric acid monoesters into a phosphate ion and a molecule with a free hydroxyl group . This action is directly opposite to that of phosphorylases and kinases, which attach phosphate groups to their...
s to pyridoxamine and absorbed in the jejunum
Jejunum
The jejunum is the middle section of the small intestine in most higher vertebrates, including mammals, reptiles, and birds. In fish, the divisions of the small intestine are not as clear and the terms middle intestine or mid-gut may be used instead of jejunum.The jejunum lies between the duodenum...
. Absorbed pyridoxamine is converted to pyridoxamine 5’-phosphate by pyridoxal kinase
Pyridoxal kinase
In enzymology, a pyridoxal kinase is an enzyme that catalyzes the chemical reactionThus, the two substrates of this enzyme are ATP and pyridoxal, whereas its two products are ADP and pyridoxal 5'-phosphate....
, which is further converted to the active pyridoxal 5-phosphate by pyridoxamine-phosphate transaminase
Pyridoxamine-phosphate transaminase
In enzymology, a pyridoxamine-phosphate transaminase is an enzyme that catalyzes the chemical reactionThus, the two substrates of this enzyme are pyridoxamine 5'-phosphate and 2-oxoglutarate, whereas its two products are pyridoxal 5'-phosphate and D-glutamate.This enzyme belongs to the family of...
or pyridoxine 5’-phosphate oxidase
Pyridoxine 5’-phosphate oxidase
Pyridoxine 5’-phosphate oxidase is an enzyme that catalyzes several reactions in the vitamin B6 metabolism pathway. Pyridoxine-5-P oxidase catalyzes the terminal step in vitamin B6 metabolism, the biosynthesis of pyridoxal-5’-phosphate, the biologically active form of vitamin B6 which acts as an...
.
Pyridoxamine is based on a pyridine
Pyridine
Pyridine is a basic heterocyclic organic compound with the chemical formula C5H5N. It is structurally related to benzene, with one C-H group replaced by a nitrogen atom...
ring structure, with hydroxyl
Hydroxyl
A hydroxyl is a chemical group containing an oxygen atom covalently bonded with a hydrogen atom. In inorganic chemistry, the hydroxyl group is known as the hydroxide ion, and scientists and reference works generally use these different terms though they refer to the same chemical structure in...
, methyl, aminomethyl, and hydroxymethyl
Hydroxymethyl
Hydroxymethyl in the field of chemistry, particularly in organic chemistry, is the name for a substituent with the structural formula -CH2-OH. The hydroxymethyl group consists of a methylene group connected to a hydroxy group. This makes the hydroxymethyl group an alcohol...
substituent
Substituent
In organic chemistry and biochemistry, a substituent is an atom or group of atoms substituted in place of a hydrogen atom on the parent chain of a hydrocarbon...
s. It differs from pyridoxine by the substituent at the 4-position. The phenol at position 3 and aminomethyl group at position 4 of its ring endow pyridoxamine with a variety of chemical properties, including the scavenging
Scavenger (chemistry)
A scavenger in chemistry is a chemical substance added to a mixture in order to remove or inactivate impurities or unwanted reaction products. Their use is wide-ranged:...
of free radical species and carbonyl species formed in sugar and lipid degradation and chelation
Chelation
Chelation is the formation or presence of two or more separate coordinate bonds between apolydentate ligand and a single central atom....
of metal ions that catalyze Amadori reactions
Amadori rearrangement
The amadori rearrangement is an organic reaction describing the acid or base catalyzed isomerization or rearrangement reaction of the N-glycoside of an aldose or the glycosylamine to the corresponding 1-amino-1-deoxy-ketose...
.
Research
Pyridoxamine can form fairly weak complexes with a number of transition metal ions, with a preference for CuCopper
Copper is a chemical element with the symbol Cu and atomic number 29. It is a ductile metal with very high thermal and electrical conductivity. Pure copper is soft and malleable; an exposed surface has a reddish-orange tarnish...
2+ and Fe
FE
Fe or FE may refer to:* Iron * Fe , the f-rune of the Younger Futhark* Fe * Fe * "Fe" , a song by Jorge González...
3+. The 3'-hydroxyl group of pyridoxamine allows for efficient hydroxyl radical
Hydroxyl radical
The hydroxyl radical, •OH, is the neutral form of the hydroxide ion . Hydroxyl radicals are highly reactive and consequently short-lived; however, they form an important part of radical chemistry. Most notably hydroxyl radicals are produced from the decomposition of hydroperoxides or, in...
scavenging.
Pyridoxamine inhibits the Maillard reaction
Maillard reaction
The Maillard reaction is a form of nonenzymatic browning similar to caramelization. It results from a chemical reaction between an amino acid and a reducing sugar, usually requiring heat....
and can block the formation of advanced glycation endproducts, which are associated with medical complications of diabetes. Pyridoxamine is hypothesized to trap intermediates in the formation of Amadori products released from glycated
Glycation
Glycation is the result of the bonding of a protein or lipid molecule with a sugar molecule, such as fructose or glucose, without the controlling action of an enzyme. All blood sugars are reducing molecules. Glycation may occur either inside the body or outside the body...
protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
s, possibly preventing the breakdown of glycated proteins by disrupting the catalysis
Catalysis
Catalysis is the change in rate of a chemical reaction due to the participation of a substance called a catalyst. Unlike other reagents that participate in the chemical reaction, a catalyst is not consumed by the reaction itself. A catalyst may participate in multiple chemical transformations....
of this process through disruptive interactions with the metal ions crucial to the redox reaction. One research study found that pyridoxamine specifically reacts with the carbonyl
Carbonyl
In organic chemistry, a carbonyl group is a functional group composed of a carbon atom double-bonded to an oxygen atom: C=O. It is common to several classes of organic compounds, as part of many larger functional groups....
group in Amadori products, but inhibition of post-Amadori reactions (that can lead to advanced glycation endproducts) is due in much greater part to the metal chelation
Chelation
Chelation is the formation or presence of two or more separate coordinate bonds between apolydentate ligand and a single central atom....
effects of pyridoxamine.
A variety of preclinical studies in animal model
Animal model
An animal model is a living, non-human animal used during the research and investigation of human disease, for the purpose of better understanding the disease without the added risk of causing harm to an actual human being during the process...
s of diabetes indicated that pyridoxamine improved kidney
Kidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...
histology
Histology
Histology is the study of the microscopic anatomy of cells and tissues of plants and animals. It is performed by examining cells and tissues commonly by sectioning and staining; followed by examination under a light microscope or electron microscope...
comparable or superior to aminoguanidine. Because of these results, pyridoxamine has been investigated for clinical utility in the treatment of diabetic nephropathy
Diabetic nephropathy
Diabetic nephropathy , also known as Kimmelstiel-Wilson syndrome, or nodular diabetic glomerulosclerosis and intercapillary glomerulonephritis, is a progressive kidney disease caused by angiopathy of capillaries in the kidney glomeruli. It is characterized by nephrotic syndrome and diffuse...
.
Pyridoxamine also inhibits the formation of advanced lipoxidation endproducts during lipid peroxidation
Lipid peroxidation
Lipid peroxidation refers to the oxidative degradation of lipids. It is the process in which free radicals "steal" electrons from the lipids in cell membranes, resulting in cell damage. This process proceeds by a free radical chain reaction mechanism...
reactions by reaction with dicarbonyl
Carbonyl
In organic chemistry, a carbonyl group is a functional group composed of a carbon atom double-bonded to an oxygen atom: C=O. It is common to several classes of organic compounds, as part of many larger functional groups....
intermediates. In other preclinical research, pyridoxamine may be efficacious in treating diabetic neuropathy
Diabetic neuropathy
Diabetic neuropathies are neuropathic disorders that are associated with diabetes mellitus. These conditions are thought to result from diabetic microvascular injury involving small blood vessels that supply nerves in addition to macrovascular conditions that can culminate in diabetic neuropathy...
and retinopathy
Retinopathy
Retinopathy is a general term that refers to some form of non-inflammatory damage to the retina of the eye. Frequently, retinopathy is an ocular manifestation of systemic disease.-Pathophysiology:Causes of retinopathy are varied:...
associated with diabetes and kidney stone
Kidney stone
A kidney stone, also known as a renal calculus is a solid concretion or crystal aggregation formed in the kidneys from dietary minerals in the urine...
disease. In one study, pyridoxamine was more effective at protecting from ionizing radiation
Ionizing radiation
Ionizing radiation is radiation composed of particles that individually have sufficient energy to remove an electron from an atom or molecule. This ionization produces free radicals, which are atoms or molecules containing unpaired electrons...
-induced gastrointestinal epithelial apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
than amifostine
Amifostine
Amifostine is a cytoprotective adjuvant used in cancer chemotherapy and radiotherapy involving DNA-binding chemotherapeutic agents. It is marketed by MedImmune under the trade name Ethyol.-Indications:...
(the only radioprotector currently Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
(FDA)-approved) due to pyridoxamine reactive oxygen species and reactive carbonyl species scavanging profile.
Patent controversy
Pyridoxamine is marketed as a dietary supplementDietary supplement
A dietary supplement, also known as food supplement or nutritional supplement, is a preparation intended to supplement the diet and provide nutrients, such as vitamins, minerals, fiber, fatty acids, or amino acids, that may be missing or may not be consumed in sufficient quantities in a person's diet...
, often as the hydrochloride
Hydrochloride
In chemistry, hydrochlorides are salts resulting, or regarded as resulting, from the reaction of hydrochloric acid with an organic base . This is also known as muriate, derived from hydrochloric acid's other name: muriatic acid....
salt, pyridoxamine dihydrochloride. However, in the United States
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...
, the FDA ruled in January 2009 that pyridoxamine must be regulated as a pharmaceutical drug because it is the active ingredient in Pyridorin, a drug designed by Biostratum, Inc., to prevent the progression of diabetic nephropathy
Diabetic nephropathy
Diabetic nephropathy , also known as Kimmelstiel-Wilson syndrome, or nodular diabetic glomerulosclerosis and intercapillary glomerulonephritis, is a progressive kidney disease caused by angiopathy of capillaries in the kidney glomeruli. It is characterized by nephrotic syndrome and diffuse...
.
A patent
Patent
A patent is a form of intellectual property. It consists of a set of exclusive rights granted by a sovereign state to an inventor or their assignee for a limited period of time in exchange for the public disclosure of an invention....
for Pyridorin, from an application by Biostratum, was published in 2004. Pyridorin had success in early clinical trials, found to be effective in slowing the progression of diabetic neuropathy in a phase II trial on 224 patients. However, the clinical trial progression of Pyridorin was stalled when it was determined that the active ingredient (pyridoxamine) was commonly available for purchase on the Internet
Internet
The Internet is a global system of interconnected computer networks that use the standard Internet protocol suite to serve billions of users worldwide...
. As the subject of an Investigational New Drug Application with the FDA, Biostratum submitted a Citizen Petition to the FDA on July 29, 2005, seeking to disallow sales of pyridoxamine-containing supplements. This petition was opposed by the Council for Responsible Nutrition, a trade association
Trade association
A trade association, also known as an industry trade group, business association or sector association, is an organization founded and funded by businesses that operate in a specific industry...
of the dietary supplement industry. On January 12, 2009, the FDA ruled that products containing pyridoxamine are excluded from the definition of dietary supplements as defined by the Dietary Supplement Health and Education Act of 1994. The FDA stated that the status of Pyridorin as an investigational new drug, as a result of an application filed by BioStratum in July 1999 and effective on September 1, 1999, meant that "the marketing of pyridoxamine in a dietary supplement is essentially equivalent to the marketing of an investigational new drug as a dietary supplement" because there was an "absence of independent, verifiable evidence that the substance was marketed as a food or a dietary supplement prior to its authorization for investigation as a new drug."
See also
- Pyridoxamine-oxaloacetate transaminasePyridoxamine-oxaloacetate transaminaseIn enzymology, a pyridoxamine-oxaloacetate transaminase is an enzyme that catalyzes the chemical reactionThus, the two substrates of this enzyme are pyridoxamine and oxaloacetate, whereas its two products are pyridoxal and L-aspartate....
- Pyridoxamine-pyruvate transaminasePyridoxamine-pyruvate transaminaseIn enzymology, a pyridoxamine-pyruvate transaminase is an enzyme that catalyzes the chemical reactionThus, the two substrates of this enzyme are pyridoxamine and pyruvate, whereas its two products are pyridoxal and L-alanine....
- Pyridoxamine-phosphate transaminasePyridoxamine-phosphate transaminaseIn enzymology, a pyridoxamine-phosphate transaminase is an enzyme that catalyzes the chemical reactionThus, the two substrates of this enzyme are pyridoxamine 5'-phosphate and 2-oxoglutarate, whereas its two products are pyridoxal 5'-phosphate and D-glutamate.This enzyme belongs to the family of...
External links
- Clinical trials testing Pyridoxamine (clinicaltrials.govClinicalTrials.govClinicalTrials.gov is a registry of clinical trials. It is run by the United States National Library of Medicine at the National Institutes of Health, and is the largest clinical trials database, currently holding registrations from over 93,000 trials from more than 170 countries in the...
):