Hydroxylation

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In chemistry, hydroxylation refers to the installation of a hydroxyl group (−OH) into an organic compound. Hydroxylations generate alcohols and phenols, which are very common functional groups. Hydroxylation confers some degree of water-solubility. Hydroxylation of a hydrocarbon is an oxidation, thus a step in degradation.

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Biological hydroxylation

In biochemistry, hydroxylation reactions are often facilitated by enzymes called hydroxylases. These enzymes insert an O atom into a C−H bond. Typical stoichiometries for the hydroxylation of a generic hydrocarbon are these:

2R3C−H + O2 → 2 R3C−OH
R3C−H + O2 + 2e− + 2H+ → R3C−OH + H2O

Since O2 itself is a slow and unselective hydroxylating agent, catalysts are required to accelerate the pace of the process and to introduce selectivity. [1]

Hydroxylation is often the first step in the degradation of organic compounds in air. Hydroxylation is important in detoxification since it converts lipophilic compounds into water-soluble (hydrophilic) products that are more readily removed by the kidneys or liver and excreted. Some drugs (for example, steroids) are activated or deactivated by hydroxylation. [2]

The principal hydroxylation catalyst in nature is cytochrome P-450, hundreds of variations of which are known. [3] Other hydroxylating agents include flavins, alpha-ketoglutarate-dependent hydroxylases (2-oxoglutarate-dependent dioxygenases), and some diiron hydroxylases. [4]

Steps in an oxygen rebound mechanism that explains many iron-catalyzed hydroxylations: H-atom abstraction, oxygen rebound, alcohol decomplexation. ORebound.png
Steps in an oxygen rebound mechanism that explains many iron-catalyzed hydroxylations: H-atom abstraction, oxygen rebound, alcohol decomplexation.

Of proteins

The hydroxylation of proteins occurs as a post-translational modification and is catalyzed by 2-oxoglutarate-dependent dioxygenases. [5] Hydroxylation improves water‐solubility, as well as affecting their structure and function.

The most frequently hydroxylated amino acid residue in human proteins is proline. This is because collagen makes up about 25–35% of the protein in our bodies and contains a hydroxyproline at almost every 3rd residue in its amino acid sequence. Collagen consists of both 3‐hydroxyproline and 4‐hydroxyproline residues. [6] Hydroxylation occurs at the γ-C atom, forming hydroxyproline (Hyp), which stabilizes the secondary structure of collagen due to the strong electronegative effects of oxygen. [7] Proline hydroxylation is also a vital component of hypoxia response via hypoxia inducible factors. In some cases, proline may be hydroxylated instead on its β-C atom. These three reactions are catalyzed by large, multi-subunit enzymes prolyl 4-hydroxylase, prolyl 3-hydroxylase, and lysyl 5-hydroxylase, respectively. These enzymes require iron (as well as molecular oxygen and α-ketoglutarate). They consume oxygen (the oxidant) and ascorbic acid (vitamin C, the reductant). Deprivation of ascorbate leads to deficiencies in proline hydroxylation, which leads to less stable collagen, which can manifest itself as the disease scurvy. Since citrus fruits are rich in vitamin C, British sailors were given limes to combat scurvy on long ocean voyages; hence, they were called "limeys". [8]

Several other amino acids aside from proline are susceptible to hydroxylation, especially lysine, asparagine, aspartate and histidine. Lysine may be hydroxylated on its δ-C atom, forming hydroxylysine (Hyl). [9] Several endogenous proteins contain hydroxyphenylalanine and hydroxytyrosine residues. These residues are formed are formed by hydroxylation of phenylalanine and tyrosine, a process in which the hydroxylation converts phenylalanine residues into tyrosine residues. [6] Hydroxylation at C-3 of tyrosine gives 3,4- dihydroxyphenylalanine (DOPA), which is a precursor to hormones and can be converted into dopamine.

Hydroxylation enzymes

Synthetic hydroxylations

Hydroxylations are well explored but only rarely practical in organic synthesis. Peroxytrifluoroacetic acid converts some arenes to phenols. Salts of peroxydisulfate converts phenols to quinols in the Elbs persulfate oxidation. Mixtures of ferrous sulfate and hydrogen peroxide, the Fenton reagent, behaves similarly. [10]

Installing hydroxyl groups into organic compounds can be effected by biomimetic catalysts, i.e. catalysts whose design is inspired by enzymes such as cytochrome P450. [11]

Whereas many hydroxylations insert O atoms into C−H bonds, some reactions add OH groups to unsaturated substrates. The Sharpless dihydroxylation is such a reaction: it converts alkenes into diols. The hydroxy groups are provided by hydrogen peroxide, which adds across the double bond of alkenes. [12]

Hydroxylation of methane

Methane is one of the most studied substrates for hydroxylation because it is abundant in natural gas. Although methane is welcome as a fuel, it would be more valuable if it could be converted to methanol. Studies on the hydroxylation of methane spans both synthetic and biological approaches. Nature has evolved enzymes called methane monooxygenases, which are efficient but impractical for commercial applications. Instead, synthetic catalysts have received much attention, but they too are not yet of practical value. [13]

Further reading

Related Research Articles

<span class="mw-page-title-main">Collagen</span> Most abundant structural protein in animals

Collagen is the main structural protein in the extracellular matrix of a body's various connective tissues. As the main component of connective tissue, it is the most abundant protein in mammals. 25% to 35% of a mammalian body's protein content is collagen. Amino acids are bound together to form a triple helix of elongated fibril known as a collagen helix. The collagen helix is mostly found in connective tissue such as cartilage, bones, tendons, ligaments, and skin. Vitamin C is vital for collagen synthesis, while Vitamin E improves its production.

<span class="mw-page-title-main">Protein primary structure</span> Linear sequence of amino acids in a peptide or protein

Protein primary structure is the linear sequence of amino acids in a peptide or protein. By convention, the primary structure of a protein is reported starting from the amino-terminal (N) end to the carboxyl-terminal (C) end. Protein biosynthesis is most commonly performed by ribosomes in cells. Peptides can also be synthesized in the laboratory. Protein primary structures can be directly sequenced, or inferred from DNA sequences.

<span class="mw-page-title-main">Tyrosine</span> Amino acid

L-Tyrosine or tyrosine or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a conditionally essential amino acid with a polar side group. The word "tyrosine" is from the Greek tyrós, meaning cheese, as it was first discovered in 1846 by German chemist Justus von Liebig in the protein casein from cheese. It is called tyrosyl when referred to as a functional group or side chain. While tyrosine is generally classified as a hydrophobic amino acid, it is more hydrophilic than phenylalanine. It is encoded by the codons UAC and UAU in messenger RNA.

Proline (symbol Pro or P) is an organic acid classed as a proteinogenic amino acid (used in the biosynthesis of proteins), although it does not contain the amino group -NH
2 but is rather a secondary amine. The secondary amine nitrogen is in the protonated form (NH2+) under biological conditions, while the carboxyl group is in the deprotonated −COO− form. The "side chain" from the α carbon connects to the nitrogen forming a pyrrolidine loop, classifying it as a aliphatic amino acid. It is non-essential in humans, meaning the body can synthesize it from the non-essential amino acid L-glutamate. It is encoded by all the codons starting with CC (CCU, CCC, CCA, and CCG).

<span class="mw-page-title-main">Catecholamine</span> Class of chemical compounds

A catecholamine is a monoamine neurotransmitter, an organic compound that has a catechol and a side-chain amine.

<span class="mw-page-title-main">Hydroxyproline</span> Chemical compound

(2S,4R)-4-Hydroxyproline, or L-hydroxyproline (C5H9O3N), is an amino acid, abbreviated as Hyp or O, e.g., in Protein Data Bank.

<span class="mw-page-title-main">Phenylalanine hydroxylase</span> Mammalian protein found in Homo sapiens

Phenylalanine hydroxylase (PAH) (EC 1.14.16.1) is an enzyme that catalyzes the hydroxylation of the aromatic side-chain of phenylalanine to generate tyrosine. PAH is one of three members of the biopterin-dependent aromatic amino acid hydroxylases, a class of monooxygenase that uses tetrahydrobiopterin (BH4, a pteridine cofactor) and a non-heme iron for catalysis. During the reaction, molecular oxygen is heterolytically cleaved with sequential incorporation of one oxygen atom into BH4 and phenylalanine substrate. In humans, mutations in its encoding gene, PAH, can lead to the metabolic disorder phenylketonuria.

<span class="mw-page-title-main">Cytochrome P450</span> Class of enzymes

Cytochromes P450 are a superfamily of enzymes containing heme as a cofactor that mostly, but not exclusively, function as monooxygenases. However, they are not omnipresent; for example, they have not been found in Escherichia coli. In mammals, these enzymes oxidize steroids, fatty acids, xenobiotics, and participate in many biosyntheses. By hydroxylation, CYP450 enzymes convert xenobiotics into hydrophilic derivatives, which are more readily excreted.

<span class="mw-page-title-main">Phenylpropanoid</span> Any organic aromatic compound with a structure based on a phenylpropane skeleton

The phenylpropanoids are a diverse family of organic compounds that are biosynthesized by plants from the amino acids phenylalanine and tyrosine in the shikimic acid pathway. Their name is derived from the six-carbon, aromatic phenyl group and the three-carbon propene tail of coumaric acid, which is the central intermediate in phenylpropanoid biosynthesis. From 4-coumaroyl-CoA emanates the biosynthesis of myriad natural products including lignols, flavonoids, isoflavonoids, coumarins, aurones, stilbenes, catechin, and phenylpropanoids. The coumaroyl component is produced from cinnamic acid.

<span class="mw-page-title-main">Methane monooxygenase</span> Class of enzymes

Methane monooxygenase (MMO) is an enzyme capable of oxidizing the C-H bond in methane as well as other alkanes. Methane monooxygenase belongs to the class of oxidoreductase enzymes.

<span class="mw-page-title-main">Tyrosine hydroxylase</span> Enzyme found in Homo sapiens that converts l-tyrosine to l-dopa, the precursor of cathecolamines

Tyrosine hydroxylase or tyrosine 3-monooxygenase is the enzyme responsible for catalyzing the conversion of the amino acid L-tyrosine to L-3,4-dihydroxyphenylalanine (L-DOPA). It does so using molecular oxygen (O2), as well as iron (Fe2+) and tetrahydrobiopterin as cofactors. L-DOPA is a precursor for dopamine, which, in turn, is a precursor for the important neurotransmitters norepinephrine (noradrenaline) and epinephrine (adrenaline). Tyrosine hydroxylase catalyzes the rate limiting step in this synthesis of catecholamines. In humans, tyrosine hydroxylase is encoded by the TH gene, and the enzyme is present in the central nervous system (CNS), peripheral sympathetic neurons and the adrenal medulla. Tyrosine hydroxylase, phenylalanine hydroxylase and tryptophan hydroxylase together make up the family of aromatic amino acid hydroxylases (AAAHs).

Lysyl hydroxylases are alpha-ketoglutarate-dependent hydroxylases enzymes that catalyze the hydroxylation of lysine to hydroxylysine. Lysyl hydroxylases require iron and vitamin C as cofactors for their oxidation activity. It takes place following collagen synthesis in the cisternae (lumen) of the rough endoplasmic reticulum (ER). There are three lysyl hydroxylases (LH1-3) encoded in the human genome, namely: PLOD1, PLOD2 and PLOD3. From PLOD2 two splice variant can be expressed, where LH2b differs from LH2a by incorporating the small exon 13A. LH1 and LH3 hydroxylate lysyl residues in the collagen triple helix, whereas LH2b hydroxylates lysyl residues in the telopeptides of collagen. In addition to its hydroxylation activity, LH3 has glucosylation activity that produces disaccharide (Glc-Gal) attached to collagen hydroxylysines.

<span class="mw-page-title-main">Tryptophan hydroxylase</span> Class of enzymes

Tryptophan hydroxylase (TPH) is an enzyme (EC 1.14.16.4) involved in the synthesis of the monoamine neurotransmitter serotonin. Tyrosine hydroxylase, phenylalanine hydroxylase, and tryptophan hydroxylase together constitute the family of biopterin-dependent aromatic amino acid hydroxylases. TPH catalyzes the following chemical reaction

Leprecan is a protein associated with osteogenesis imperfecta type VIII.

<span class="mw-page-title-main">Cholesterol 24-hydroxylase</span> Protein family

Cholesterol 24-hydroxylase, also commonly known as cholesterol 24S-hydroxylase, cholesterol 24-monooxygenase, CYP46, or CYP46A1, is an enzyme that catalyzes the conversion of cholesterol to 24S-hydroxycholesterol. It is responsible for the majority of cholesterol turnover in the human central nervous system. The systematic name of this enzyme class is cholesterol,NADPH:oxygen oxidoreductase (24-hydroxylating).

<span class="mw-page-title-main">Procollagen-proline dioxygenase</span> Enzyme

Procollagen-proline dioxygenase, commonly known as prolyl hydroxylase, is a member of the class of enzymes known as alpha-ketoglutarate-dependent hydroxylases. These enzymes catalyze the incorporation of oxygen into organic substrates through a mechanism that requires alpha-Ketoglutaric acid, Fe2+, and ascorbate. This particular enzyme catalyzes the formation of (2S, 4R)-4-hydroxyproline, a compound that represents the most prevalent post-translational modification in the human proteome.

<span class="mw-page-title-main">CYP4F2</span> Enzyme protein in the species Homo sapiens

Cytochrome P450 4F2 is a protein that in humans is encoded by the CYP4F2 gene. This protein is an enzyme, a type of protein that catalyzes chemical reactions inside cells. This specific enzyme is part of the superfamily of cytochrome P450 (CYP) enzymes, and the encoding gene is part of a cluster of cytochrome P450 genes located on chromosome 19.

A transition metal oxo complex is a coordination complex containing an oxo ligand. Formally O2–, an oxo ligand can be bound to one or more metal centers, i.e. it can exist as a terminal or (most commonly) as bridging ligands. Oxo ligands stabilize high oxidation states of a metal. They are also found in several metalloproteins, for example in molybdenum cofactors and in many iron-containing enzymes. One of the earliest synthetic compounds to incorporate an oxo ligand is potassium ferrate (K2FeO4), which was likely prepared by Georg E. Stahl in 1702.

<span class="mw-page-title-main">Biopterin-dependent aromatic amino acid hydroxylase</span>

Biopterin-dependent aromatic amino acid hydroxylases (AAAH) are a family of aromatic amino acid hydroxylase enzymes which includes phenylalanine 4-hydroxylase, tyrosine 3-hydroxylase, and tryptophan 5-hydroxylase. These enzymes primarily hydroxylate the amino acids L-phenylalanine, L-tyrosine, and L-tryptophan, respectively.

Cytochrome P450 omega hydroxylases, also termed cytochrome P450 ω-hydroxylases, CYP450 omega hydroxylases, CYP450 ω-hydroxylases, CYP omega hydroxylase, CYP ω-hydroxylases, fatty acid omega hydroxylases, cytochrome P450 monooxygenases, and fatty acid monooxygenases, are a set of cytochrome P450-containing enzymes that catalyze the addition of a hydroxyl residue to a fatty acid substrate. The CYP omega hydroxylases are often referred to as monoxygenases; however, the monooxygenases are CYP450 enzymes that add a hydroxyl group to a wide range of xenobiotic and naturally occurring endobiotic substrates, most of which are not fatty acids. The CYP450 omega hydroxylases are accordingly better viewed as a subset of monooxygenases that have the ability to hydroxylate fatty acids. While once regarded as functioning mainly in the catabolism of dietary fatty acids, the omega oxygenases are now considered critical in the production or break-down of fatty acid-derived mediators which are made by cells and act within their cells of origin as autocrine signaling agents or on nearby cells as paracrine signaling agents to regulate various functions such as blood pressure control and inflammation.

References

  1. 1 2 Huang, X.; Groves, J. T. (2017). "Beyond ferryl-mediated hydroxylation: 40 years of the rebound mechanism and C–H activation". Journal of Biological Inorganic Chemistry. 22 (2–3): 185–207. doi:10.1007/s00775-016-1414-3. PMC   5350257 . PMID   27909920.
  2. ↑ Cerniglia, Carl E. (1992). "Biodegradation of polycyclic aromatic hydrocarbons". Biodegradation. 3 (2–3): 351–368. doi:10.1007/BF00129093. S2CID   25516145.
  3. ↑ Ortiz De Montellano, Paul R. (2010). "Hydrocarbon Hydroxylation by Cytochrome P450 Enzymes". Chemical Reviews. 110 (2): 932–948. doi:10.1021/cr9002193. PMC   2820140 . PMID   19769330.
  4. ↑ Nelson, D. L.; Cox, M. M. "Lehninger, Principles of Biochemistry" 3rd Ed. Worth Publishing: New York, 2000. ISBN   1-57259-153-6.[ page needed ]
  5. ↑ Zurlo, Giada; Guo, Jianping; Takada, Mamoru; Wei, Wenyi; Zhang, Qing (December 2016). "New Insights into Protein Hydroxylation and Its Important Role in Human Diseases". Biochimica et Biophysica Acta (BBA) - Reviews on Cancer. 1866 (2): 208–220. doi:10.1016/j.bbcan.2016.09.004. ISSN   0006-3002. PMC   5138100 . PMID   27663420.
  6. 1 2 T. Shantha Raju (2019), "Hydroxylation of Proteins", Co- and Post-Translational Modifications of Therapeutic Antibodies and Proteins, John Wiley & Sons, pp. 119–131, doi:10.1002/9781119053354.ch10, ISBN   978-1-119-05335-4, S2CID   243626930
  7. ↑ Holmgren, Steven K; Bretscher, Lynn E; Taylor, Kimberly M; Raines, Ronald T (1999). "A hyperstable collagen mimic". Chemistry & Biology. 6 (2): 63–70. doi: 10.1016/S1074-5521(99)80003-9 . PMID   10021421.
  8. ↑ Voet, Donald; Voet, Judith G.; Pratt, Charlotte W. (2016). Principles of Biochemistry. Wiley. p. 143. ISBN   978-1-119-45166-2.
  9. ↑ Hausinger RP (January–February 2004). "Fe(II)/α-ketoglutarate-dependent hydroxylases and related enzymes". Crit. Rev. Biochem. Mol. Biol. 39 (1): 21–68. doi:10.1080/10409230490440541. PMID   15121720. S2CID   85784668.
  10. ↑ Smith, Michael B.; March, Jerry (2007), Advanced Organic Chemistry: Reactions, Mechanisms, and Structure (6th ed.), New York: Wiley-Interscience, p. 964, ISBN   978-0-471-72091-1
  11. ↑ Jia, Chengguo; Kitamura, Tsugio; Fujiwara, Yuzo (2001). "Catalytic Functionalization of Arenes and Alkanes via C−H Bond Activation". Accounts of Chemical Research. 34 (8): 633–639. doi:10.1021/ar000209h. PMID   11513570.
  12. ↑ Kolb, Hartmuth C.; Vannieuwenhze, Michael S.; Sharpless, K. Barry (1994). "Catalytic Asymmetric Dihydroxylation". Chemical Reviews. 94 (8): 2483–2547. doi:10.1021/cr00032a009.
  13. ↑ Dummer, Nicholas F.; Willock, David J.; He, Qian; Howard, Mark J.; Lewis, Richard J.; Qi, Guodong; Taylor, Stuart H.; Xu, Jun; Bethell, Don; Kiely, Christopher J.; Hutchings, Graham J. (2023). "Methane Oxidation to Methanol". Chemical Reviews. 123 (9): 6359–6411. doi:10.1021/acs.chemrev.2c00439. PMC   10176486 . PMID   36459432.
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