Homoserine (also called isothreonine) is an α-amino acid with the chemical formula HO2CCH(NH2)CH2CH2OH. It differs from the proteinogenic amino acid serine by insertion of an additional -CH2- unit into the backbone. Homoserine, or its lactone form, is the product of a cyanogen bromide cleavage of a peptide by degradation of methionine.
Homoserine is an intermediate in the biosynthesis of three essential amino acids: methionine, threonine (an isomer of homoserine), and isoleucine.[1] Its complete biosynthetic pathway includes glycolysis, the tricarboxylic acid (TCA) or citric acid cycle or the Krebs cycle, and the aspartate metabolic pathway. It forms by two reductions of aspartic acid via the intermediacy of aspartate semialdehyde. Specifically, the enzyme homoserine dehydrogenase, in association with NADPH, catalyzes a reversible reaction that interconverts L-aspartate-4-semialdehyde to L-homoserine. Then, two other enzymes, homoserine kinase and homoserine o-succinyl transferase use homoserine as a substrate and produce phosphohomoserine and o-succinyl homoserine respectively.[2]
Homoserine Usage
Commercially, homoserine can serve as precursor to the synthesis of isobutanol and 1,4-butanediol.[3] Purified homoserine is used in enzyme structural studies.[4] Also, homoserine has played important roles in studies to elucidate peptide synthesis and synthesis of proteoglycan glycopeptides.[5] Although there are several synthetic approaches to homoserine production, there is interest to generate bacterial cell lines that can make copious amounts of this amino acid and its products.[2][3]
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Biosynthetic Pathway for Homoserine in Bacterial Cells edit
Oxaloacetate, from the citric acid cycle, is converted to aspartate, then the subsequent reactions that lead to the production lysine, methionine, threonine and isoleucine comprise the aspartate metabolic pathway. First, aspartate is converted to L-aspartyl-4-phosphate by enzyme aspartate kinase or aspartokinase. Next, L-aspartyl-4-phosphate is converted to L-aspartate-4-semialdehyde by aspartyl semialdehyde dehydrogenase. L-aspartate-4-semialdehyde is an important point in the biosynthesis of amino acids as some L-aspartate-4-semialdehyde molecules follow the pathway to producing L-Lysine and the other molecules are converted to homoserine by homoserine dehydrogenase. L-Homoserine is another branching point in amino acid synthesis. Some homoserine molecules are acted upon by homoserine kinase and produce phosphohomoserine or homoserine-phosphate, followed by threonine synthase to yield L-Threonine. Threonine can subsequently be converted in a three-step reaction to L-Isoleucine. The other path for homoserine is to be converted to o-succinyl homoserine by homoserine o-succinyl transferase, followed by three additional reactions to L-Methionine.[6]
The enzymes involved in this pathway are regulated in part by allosteric, noncompetitive inhibition and competitive inhibition. Homoserine allosterically inhibits aspartate kinase and glutamate dehydrogenase. [2] Glutamate dehydrogenase reversibly converts glutamate to α-ketoglutarate and α-ketoglutarate coverts to oxaloacetate through the citric cycle. Threonine acts as another allosteric inhibitor of aspartate kinase and homoserine dehydrogenase, but it is a competitive inhibitor of homoserine kinase.[6]
References edit
- ^ Tanaka, Masao; Kishi, Teruo; Kinoshita, Shukuo (1961-09). "Studies on the Synthesis of l -Amino Acids: Part III. A Synthesis of l -Homoserine from l -Aspartic Acid". Agricultural and Biological Chemistry. 25 (9): 678–679. doi:10.1080/00021369.1961.10857862. ISSN 0002-1369.
{{cite journal}}: Check date values in:|date=(help) - ^ a b c Liu, Peng; Zhang, Bo; Yao, Zhen-Hao; Liu, Zhi-Qiang; Zheng, Yu-Guo (2020-10). Zhou, Ning-Yi (ed.). "Multiplex Design of the Metabolic Network for Production of l -Homoserine in Escherichia coli". Applied and Environmental Microbiology. 86 (20). doi:10.1128/AEM.01477-20. ISSN 0099-2240.
{{cite journal}}: Check date values in:|date=(help) - ^ a b Huang, Jian-Feng; Zhang, Bo; Shen, Zhen-Yang; Liu, Zhi-Qiang; Zheng, Yu-Guo (2018-07). "Metabolic engineering of E. coli for the production of O-succinyl-l-homoserine with high yield". 3 Biotech. 8 (7): 310. doi:10.1007/s13205-018-1332-x. ISSN 2190-572X. PMC 6037649. PMID 30002999.
{{cite journal}}: Check date values in:|date=(help)CS1 maint: PMC format (link) - ^ Akai, Shota; Ikushiro, Hiroko; Sawai, Taiki; Yano, Takato; Kamiya, Nobuo; Miyahara, Ikuko (2019-02-01). "The crystal structure of homoserine dehydrogenase complexed with l -homoserine and NADPH in a closed form". The Journal of Biochemistry. 165 (2): 185–195. doi:10.1093/jb/mvy094. ISSN 0021-924X.
- ^ Yang, Weizhun; Ramadan, Sherif; Yang, Bo; Yoshida, Keisuke; Huang, Xuefei (2016-12-02). "Homoserine as an Aspartic Acid Precursor for Synthesis of Proteoglycan Glycopeptide Containing Aspartic Acid and a Sulfated Glycan Chain". The Journal of Organic Chemistry. 81 (23): 12052–12059. doi:10.1021/acs.joc.6b02441. ISSN 0022-3263.
- ^ a b Petit, Cecile; Kim, Younghwa; Lee, Sung-Kwon; Brown, Jake; Larsen, Erik; Ronning, Donald R.; Suh, Joo-Won; Kang, Choong-Min (2018-01-31). "Reduction of Feedback Inhibition in Homoserine Kinase (ThrB) of Corynebacterium glutamicum Enhances l -Threonine Biosynthesis". ACS Omega. 3 (1): 1178–1186. doi:10.1021/acsomega.7b01597. ISSN 2470-1343.