Hydroxylation

Hydroxylation is a chemical process that introduces a hydroxyl group (-OH) 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. It is extremely important in detoxification since hydroxylation 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.

Hydroxylation and hydroxylases are not to be confused with hydrolysis and hydrolases.

Biological hydroxylation

The hydroxylation process involves conversion of a CH group into a COH group. Hydroxylation is an oxidative process. The oxygen that is inserted into the C-H bond is usually derived from atmospheric oxygen (O2). 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]

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

Steps in an oxygen rebound mechanism that explains many iron-catalyzed hydroxylations: H-atom abstraction, oxygen rebound, alcohol decomplexation.[1]

Of proteins

The hydroxylation of proteins occurs as a post-translational modification, and is catalyzed by 2-oxoglutarate-dependent dioxygenases. [3] When molecules are hydroxylated, they become more water‐soluble, which affects their structure and function. It can take place on several amino acids, like lysine, asparagine, aspartate and histidine, but the most frequently hydroxylated amino acid residue in human proteins is proline. This is due to the fact that 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. [4] 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.[5] 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. Lysine may also be hydroxylated on its δ-C atom, forming hydroxylysine (Hyl).[6]

These three reactions are catalyzed by very large, multi-subunit enzymes prolyl 4-hydroxylase, prolyl 3-hydroxylase and lysyl 5-hydroxylase, respectively. These reactions require iron (as well as molecular oxygen and α-ketoglutarate) to carry out the oxidation, and use ascorbic acid (vitamin C) to return the iron to its reduced state. 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".

Several endogenous proteins contain hydroxyphenylalanine and hydroxytyrosine residues. These residues are formed due to the hydroxylation of phenylalanine and tyrosine, a process in which the hydroxylation converts phenylalanine residues into tyrosine residues. This is very important in living organisms to help them control excess amounts of phenylalanine residues.[7] Hydroxylation of tyrosine residues is also very vital in living organisms because hydroxylation at C-3 of tyrosine creates 3,4- dihydroxy phenylalanine (DOPA), which is a precursor to hormones and can be converted into dopamine.

Examples
  • One example of non-biological hydroxylation is the hydrogen peroxide hydroxylation of phenol to form hydroquinone.
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References
  1. Huang, X.; Groves, J. T. (2017). "Beyond ferryl-mediated hydroxylation: 40 years of the rebound mechanism and C–H activation". JBIC Journal of Biological Inorganic Chemistry. 22 (2–3): 185–207. doi:10.1007/s00775-016-1414-3. PMC 5350257. PMID 27909920.CS1 maint: uses authors parameter (link)
  2. Nelson, D. L.; Cox, M. M. "Lehninger, Principles of Biochemistry" 3rd Ed. Worth Publishing: New York, 2000. ISBN 1-57259-153-6.
  3. 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.
  4. Co and Post-Translational Modifications of Therapeutic Antibodies and Proteins, John Wiley & Sons, Ltd, pp. 119–131, 2019, doi:10.1002/9781119053354.ch10, ISBN 978-1-119-05335-4 Missing or empty |title= (help); |chapter= ignored (help)
  5. 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.
  6. 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.CS1 maint: uses authors parameter (link)
  7. Co and Post-Translational Modifications of Therapeutic Antibodies and Proteins, John Wiley & Sons, Ltd, pp. 119–131, 2019, doi:10.1002/9781119053354.ch10, ISBN 978-1-119-05335-4 Missing or empty |title= (help); |chapter= ignored (help)
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