Hydroxyproline
Encyclopedia
-4-Hydroxyproline, or L-hydroxyproline (C
5H
9O
3N
), is a common non-proteinogenic amino acid, abbreviated as HYP, e.g., in Protein Data Bank
.
isolated hydroxyproline from hydrolized gelatin. In 1905, Hermann Leuchs
synthesized a racemic mixture of 4-hydroxyproline.
Hydroxyproline differs from proline
by the presence of a hydroxyl (OH) group attached to the gamma carbon atom.
of the amino acid proline
by the enzyme prolyl hydroxylase
following protein synthesis (as a post-translational modification). The enzyme catalysed reaction takes place in the lumen
of the endoplasmic reticulum. Although it is not directly incorporated into proteins, hydroxyproline comprises roughly 4% of all amino acids found in animal tissue, more than seven amino acids which are directly incorporated.
Hydroxyproline is a major component of the protein
collagen
. Hydroxyproline and proline play key roles for collagen stability. They permit the sharp twisting of the collagen helix. In the canonical collagen Xaa-Yaa-Gly triad (where Xaa and Yaa are any amino acid), a proline occupying the Yaa position is hydroxylated to give a Xaa-Hyp-Gly sequence. This modification of the proline residue increases the stability of the collagen triple helix
. It was initially proposed that the stabilization was due to water molecules forming a hydrogen bonding network linking the prolyl hydroxyl groups and the main-chain carbonyl groups. It was subsequently shown that the increase in stability is primarily through stereoelectronic effects and that hydration of the hydroxyproline residues provides little or no additional stability. In addition to collagen, the mammalian proteins elastin
and argonaute 2
have collagen-like domains in which hydroxyproline is formed. Some snail poisons, conotoxin
s, contain hydroxyproline, but lack collagen-like sequences.
Hydroxylation of proline has been shown to be involved in targeting Hypoxia-inducible factor (HIF) alpha subunit (HIF-1 alpha) for degradation by proteolysis
. Under normoxia (normal oxygen conditions) EGLN1
http://www.ncbi.nlm.nih.gov/gene/54583 protein hydroxylates the proline at the 564 position of HIF-1 alpha, which allows ubiquitylation by the von Hippel-Lindau tumor suppressor
(pVHL) and subsequent targeting for proteasome
degradation.
Hydroxyproline is found in few proteins other than collagen. For this reason, hydroxyproline content has been used as an indicator to determine collagen
and/or gelatin
amount.
Hydroxyproline rich glycoprotein
s are also found in plant cell walls.
hydroxylation requires ascorbic acid
(vitamin C
). The most obvious, first effects (gum and hair problems) of absence of ascorbic acid
in humans come from the resulting defect in hydroxylation
of proline
residues of collagen
, with reduced stability
of the collagen molecule, causing scurvy
.
Increased serum and urine levels of hydroxyproline have also been demonstrated in Paget's disease
.
cell wall
s and is postulated to have a role in silica deposition. Hydroxyproline is also found in the walls of oomycetes, fungus-like protists related to diatoms. cis-4-hydroxyproline (2S, 4S) is found in the toxic cyclic peptides from Amanita mushrooms (e.g., alpha-amanitin and phalloidin).
Carbon
Carbon is the chemical element with symbol C and atomic number 6. As a member of group 14 on the periodic table, it is nonmetallic and tetravalent—making four electrons available to form covalent chemical bonds...
5H
Hydrogen
Hydrogen is the chemical element with atomic number 1. It is represented by the symbol H. With an average atomic weight of , hydrogen is the lightest and most abundant chemical element, constituting roughly 75% of the Universe's chemical elemental mass. Stars in the main sequence are mainly...
9O
Oxygen
Oxygen is the element with atomic number 8 and represented by the symbol O. Its name derives from the Greek roots ὀξύς and -γενής , because at the time of naming, it was mistakenly thought that all acids required oxygen in their composition...
3N
Nitrogen
Nitrogen is a chemical element that has the symbol N, atomic number of 7 and atomic mass 14.00674 u. Elemental nitrogen is a colorless, odorless, tasteless, and mostly inert diatomic gas at standard conditions, constituting 78.08% by volume of Earth's atmosphere...
), is a common non-proteinogenic amino acid, abbreviated as HYP, e.g., in Protein Data Bank
Protein Data Bank
The Protein Data Bank is a repository for the 3-D structural data of large biological molecules, such as proteins and nucleic acids....
.
Structure and discovery
In 1902, Hermann Emil FischerHermann Emil Fischer
Hermann Emil Fischer, Emil Fischer was a German chemist and 1902 recipient of the Nobel Prize in Chemistry. He discovered the Fischer esterification. He developed the Fischer projection, a symbolic way of drawing asymmetric carbon atoms.-Early years:Fischer was born in Euskirchen, near Cologne,...
isolated hydroxyproline from hydrolized gelatin. In 1905, Hermann Leuchs
Hermann Leuchs
-Life:Leuchs studied chemistry at the University of Munich from 1898 till he changed to the University of Berlin He earned his Ph.D. with Hermann Emil Fischer in 1902 in Berlin. He steadily advanced in the hierarchy of the university, 1910 lecturer, assistant professor in 1914 and full professor in...
synthesized a racemic mixture of 4-hydroxyproline.
Hydroxyproline differs from proline
Proline
Proline is an α-amino acid, one of the twenty DNA-encoded amino acids. Its codons are CCU, CCC, CCA, and CCG. It is not an essential amino acid, which means that the human body can synthesize it. It is unique among the 20 protein-forming amino acids in that the α-amino group is secondary...
by the presence of a hydroxyl (OH) group attached to the gamma carbon atom.
Production and function
Hydroxyproline is produced by hydroxylationHydroxylation
Hydroxylation is a chemical process that introduces a hydroxyl group into an organic compound. In biochemistry, hydroxylation reactions are often facilitated by enzymes called hydroxylases. Hydroxylation is the first step in the oxidative degradation of organic compounds in air...
of the amino acid proline
Proline
Proline is an α-amino acid, one of the twenty DNA-encoded amino acids. Its codons are CCU, CCC, CCA, and CCG. It is not an essential amino acid, which means that the human body can synthesize it. It is unique among the 20 protein-forming amino acids in that the α-amino group is secondary...
by the enzyme prolyl hydroxylase
Prolyl hydroxylase
Prolyl hydroxylase is an enzyme involved in the production of collagen, acting to hydroxylate proline to hydroxyproline....
following protein synthesis (as a post-translational modification). The enzyme catalysed reaction takes place in the lumen
Lumen (anatomy)
A lumen in biology is the inside space of a tubular structure, such as an artery or intestine...
of the endoplasmic reticulum. Although it is not directly incorporated into proteins, hydroxyproline comprises roughly 4% of all amino acids found in animal tissue, more than seven amino acids which are directly incorporated.
Hydroxyproline is a major component of the 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...
collagen
Collagen
Collagen is a group of naturally occurring proteins found in animals, especially in the flesh and connective tissues of mammals. It is the main component of connective tissue, and is the most abundant protein in mammals, making up about 25% to 35% of the whole-body protein content...
. Hydroxyproline and proline play key roles for collagen stability. They permit the sharp twisting of the collagen helix. In the canonical collagen Xaa-Yaa-Gly triad (where Xaa and Yaa are any amino acid), a proline occupying the Yaa position is hydroxylated to give a Xaa-Hyp-Gly sequence. This modification of the proline residue increases the stability of the collagen triple helix
Triple helix
In geometry, a triple helix is a set of three congruent geometrical helices with the same axis, differing by a translation along the axis. Structures in the form of a triple helix include:* collagen helix...
. It was initially proposed that the stabilization was due to water molecules forming a hydrogen bonding network linking the prolyl hydroxyl groups and the main-chain carbonyl groups. It was subsequently shown that the increase in stability is primarily through stereoelectronic effects and that hydration of the hydroxyproline residues provides little or no additional stability. In addition to collagen, the mammalian proteins elastin
Elastin
Elastin is a protein in connective tissue that is elastic and allows many tissues in the body to resume their shape after stretching or contracting. Elastin helps skin to return to its original position when it is poked or pinched. Elastin is also an important load-bearing tissue in the bodies of...
and argonaute 2
Argonaute
Argonaute proteins are the catalytic components of the RNA-induced silencing complex , the protein complex responsible for the gene silencing phenomenon known as RNA interference . Argonaute proteins bind different classes of small non-coding RNAs, including microRNAs , small interfering RNAs and...
have collagen-like domains in which hydroxyproline is formed. Some snail poisons, conotoxin
Conotoxin
A conotoxin is one of a group of neurotoxic peptides isolated from the venom of the marine cone snail, genus Conus.Conotoxins, which are peptides consisting of 10 to 30 amino acid residues, typically have one or more disulfide bonds. Conotoxins have a variety of mechanisms of actions, most of...
s, contain hydroxyproline, but lack collagen-like sequences.
Hydroxylation of proline has been shown to be involved in targeting Hypoxia-inducible factor (HIF) alpha subunit (HIF-1 alpha) for degradation by proteolysis
Proteolysis
Proteolysis is the directed degradation of proteins by cellular enzymes called proteases or by intramolecular digestion.-Purposes:Proteolysis is used by the cell for several purposes...
. Under normoxia (normal oxygen conditions) EGLN1
EGLN1
Egl nine homolog 1 also known as prolyl hydroxylase domain-containing protein 2 or hypoxia-inducible factor prolyl hydroxylase 2 is an enzyme that in humans is encoded by the EGLN1 gene....
http://www.ncbi.nlm.nih.gov/gene/54583 protein hydroxylates the proline at the 564 position of HIF-1 alpha, which allows ubiquitylation by the von Hippel-Lindau tumor suppressor
Von Hippel-Lindau tumor suppressor
The Von Hippel–Lindau tumor suppressor also known as pVHL is a protein that in humans is encoded by the VHL gene. Mutations of the VHL gene are associated with Von Hippel–Lindau disease....
(pVHL) and subsequent targeting for proteasome
Proteasome
Proteasomes are very large protein complexes inside all eukaryotes and archaea, and in some bacteria. In eukaryotes, they are located in the nucleus and the cytoplasm. The main function of the proteasome is to degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks...
degradation.
Hydroxyproline is found in few proteins other than collagen. For this reason, hydroxyproline content has been used as an indicator to determine collagen
Collagen
Collagen is a group of naturally occurring proteins found in animals, especially in the flesh and connective tissues of mammals. It is the main component of connective tissue, and is the most abundant protein in mammals, making up about 25% to 35% of the whole-body protein content...
and/or gelatin
Gelatin
Gelatin is a translucent, colorless, brittle , flavorless solid substance, derived from the collagen inside animals' skin and bones. It is commonly used as a gelling agent in food, pharmaceuticals, photography, and cosmetic manufacturing. Substances containing gelatin or functioning in a similar...
amount.
Hydroxyproline rich glycoprotein
Glycoprotein
Glycoproteins are proteins that contain oligosaccharide chains covalently attached to polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. In proteins that have segments extending...
s are also found in plant cell walls.
Clinical significance
ProlineProline
Proline is an α-amino acid, one of the twenty DNA-encoded amino acids. Its codons are CCU, CCC, CCA, and CCG. It is not an essential amino acid, which means that the human body can synthesize it. It is unique among the 20 protein-forming amino acids in that the α-amino group is secondary...
hydroxylation requires ascorbic acid
Ascorbic acid
Ascorbic acid is a naturally occurring organic compound with antioxidant properties. It is a white solid, but impure samples can appear yellowish. It dissolves well in water to give mildly acidic solutions. Ascorbic acid is one form of vitamin C. The name is derived from a- and scorbutus , the...
(vitamin C
Vitamin C
Vitamin C or L-ascorbic acid or L-ascorbate is an essential nutrient for humans and certain other animal species. In living organisms ascorbate acts as an antioxidant by protecting the body against oxidative stress...
). The most obvious, first effects (gum and hair problems) of absence of ascorbic acid
Ascorbic acid
Ascorbic acid is a naturally occurring organic compound with antioxidant properties. It is a white solid, but impure samples can appear yellowish. It dissolves well in water to give mildly acidic solutions. Ascorbic acid is one form of vitamin C. The name is derived from a- and scorbutus , the...
in humans come from the resulting defect in hydroxylation
Hydroxylation
Hydroxylation is a chemical process that introduces a hydroxyl group into an organic compound. In biochemistry, hydroxylation reactions are often facilitated by enzymes called hydroxylases. Hydroxylation is the first step in the oxidative degradation of organic compounds in air...
of proline
Proline
Proline is an α-amino acid, one of the twenty DNA-encoded amino acids. Its codons are CCU, CCC, CCA, and CCG. It is not an essential amino acid, which means that the human body can synthesize it. It is unique among the 20 protein-forming amino acids in that the α-amino group is secondary...
residues of collagen
Collagen
Collagen is a group of naturally occurring proteins found in animals, especially in the flesh and connective tissues of mammals. It is the main component of connective tissue, and is the most abundant protein in mammals, making up about 25% to 35% of the whole-body protein content...
, with reduced stability
Chemical stability
Chemical stability when used in the technical sense in chemistry, means thermodynamic stability of a chemical system.Thermodynamic stability occurs when a system is in its lowest energy state, or chemical equilibrium with its environment. This may be a dynamic equilibrium, where individual atoms...
of the collagen molecule, causing scurvy
Scurvy
Scurvy is a disease resulting from a deficiency of vitamin C, which is required for the synthesis of collagen in humans. The chemical name for vitamin C, ascorbic acid, is derived from the Latin name of scurvy, scorbutus, which also provides the adjective scorbutic...
.
Increased serum and urine levels of hydroxyproline have also been demonstrated in Paget's disease
Paget's disease
Sir James Paget, a surgeon and pathologist, described several diseases, including:* Paget's disease of bone * Paget's disease of the breast* Paget-Schroetter disease* Extramammary Paget's disease...
.
Other hydroxyprolines
Other hydroxyprolines also exist in nature, the most notable ones being 2,3-cis-, 3,4-trans-, and 3,4-dihydroxyproline, which occurs in diatomDiatom
Diatoms are a major group of algae, and are one of the most common types of phytoplankton. Most diatoms are unicellular, although they can exist as colonies in the shape of filaments or ribbons , fans , zigzags , or stellate colonies . Diatoms are producers within the food chain...
cell wall
Cell wall
The cell wall is the tough, usually flexible but sometimes fairly rigid layer that surrounds some types of cells. It is located outside the cell membrane and provides these cells with structural support and protection, and also acts as a filtering mechanism. A major function of the cell wall is to...
s and is postulated to have a role in silica deposition. Hydroxyproline is also found in the walls of oomycetes, fungus-like protists related to diatoms. cis-4-hydroxyproline (2S, 4S) is found in the toxic cyclic peptides from Amanita mushrooms (e.g., alpha-amanitin and phalloidin).