{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T02:50:01Z","timestamp":1760237401307,"version":"build-2065373602"},"reference-count":52,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2020,4,7]],"date-time":"2020-04-07T00:00:00Z","timestamp":1586217600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Symmetry"],"abstract":"<jats:p>Biochirality is the subject of distinct branches of science, including biophysics, biochemistry, the stereochemistry of protein folding, neuroscience, brain functional laterality and bioinformatics. At the protein level, biochirality is closely associated with various post-translational modifications (PTMs) accompanied by the non-equilibrium phase transitions (PhTs NE). PTMs NE support the dynamic balance of the prevalent chirality of enzymes and their substrates. The stereoselective nature of most biochemical reactions is evident in the enzymatic (Enz) and spontaneous (Sp) PTMs (PTMs Enz and PTMs Sp) of proteins. Protein chirality, which embraces biophysics and biochemistry, is a subject of this review. In this broad field, we focus attention to the amyloid-beta (A\u03b2) peptide, known for its essential cellular functions and associations with neuropathology. The widely discussed amyloid cascade hypothesis (ACH) of Alzheimer\u2019s disease (AD) states that disease pathogenesis is initiated by the oligomerization and subsequent aggregation of the A\u03b2 peptide into plaques. The racemization-induced aggregation of protein and RNA have been extensively studied in the search for the contribution of spontaneous stochastic stereo-specific mechanisms that are common for both kinds of biomolecules. The failure of numerous A\u03b2 drug-targeting therapies requires the reconsolidation of the ACH with the concept of PTMs Sp. The progress in methods of chiral discrimination can help overcome previous limitations in the understanding of AD pathogenesis. The primary target of attention becomes the network of stereospecific PTMs that affect the aggregation of many pathogenic agents, including A\u03b2. Extensive recent experimental results describe the truncated, isomerized and racemized forms of A\u03b2 and the interplay between enzymatic and PTMs Sp. Currently, accumulated data suggest that non-enzymatic PTMs Sp occur in parallel to an existing metabolic network of enzymatic pathways, meaning that the presence and activity of enzymes does not prevent non-enzymatic reactions from occurring. PTMs Sp impact the functions of many proteins and peptides, including A\u03b2. This is in logical agreement with the silently accepted racemization hypothesis of protein aggregation (RHPA). Therefore, the ACH of AD should be complemented by the concept of PTMs Sp and RHPA.<\/jats:p>","DOI":"10.3390\/sym12040585","type":"journal-article","created":{"date-parts":[[2020,4,9]],"date-time":"2020-04-09T14:42:03Z","timestamp":1586443323000},"page":"585","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Chiral Interface of Amyloid Beta (A\u03b2): Relevance to Protein Aging, Aggregation and Neurodegeneration"],"prefix":"10.3390","volume":"12","author":[{"given":"Victor V.","family":"Dyakin","sequence":"first","affiliation":[{"name":"Departmemts: Virtual Reality Perception Lab. (VV. Dyakin) and Center for Neurochemistry (A. Lajtha), The Nathan S. Kline Institute for Psychiatric Research (NKI), Orangeburg, NY 10962, USA"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3379-8966","authenticated-orcid":false,"given":"Thomas M.","family":"Wisniewski","sequence":"additional","affiliation":[{"name":"Departments of Neurology, Pathology and Psychiatry, Center for Cognitive Neurology, New York University School of Medicine, New York, NY 10016, USA"}]},{"given":"Abel","family":"Lajtha","sequence":"additional","affiliation":[{"name":"Departmemts: Virtual Reality Perception Lab. (VV. Dyakin) and Center for Neurochemistry (A. Lajtha), The Nathan S. Kline Institute for Psychiatric Research (NKI), Orangeburg, NY 10962, USA"}]}],"member":"1968","published-online":{"date-parts":[[2020,4,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Schreiner, E., Trabuco, L.G., Freddolino, P.L., and Schulten, K. (2011). Stereochemical errors and their implications for molecular dynamics simulations. BMC Bioinform., 12.","DOI":"10.1186\/1471-2105-12-190"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/S0006-291X(86)80329-1","article-title":"The presence of free D-aspartic acid in rodents and man","volume":"141","author":"Dunlop","year":"1986","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1545","DOI":"10.1039\/C7MB00249A","article-title":"Phosphorylation of a full-length amyloid-\u03b2 peptide modulates its amyloid aggregation, cell binding and neurotoxic properties","volume":"13","author":"Jamasbi","year":"2017","journal-title":"Mol. BioSyst."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"18494","DOI":"10.1038\/s41598-019-54918-0","article-title":"Structural and biochemical basis of the formation of isoaspartate in the complementarity-determining region of antibody 64M-5 Fab","volume":"9","author":"Yokoyama","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1042\/BST0380539","article-title":"Alzheimer\u2019s disease and amyloid \u03b2-peptide deposition in the brain: A matter of \u2018aging\u2019?","volume":"38","author":"Moro","year":"2010","journal-title":"Biochem. Soc. Trans."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.neuint.2017.08.007","article-title":"APP\/A\u03b2 structural diversity and Alzheimer\u2019s disease pathogenesis","volume":"110","author":"Roher","year":"2018","journal-title":"Neurochem. Int."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1112","DOI":"10.1016\/j.clinbiochem.2006.07.009","article-title":"Biochemistry of amino acid racemization and clinical application to musculoskeletal disease","volume":"39","author":"McCudden","year":"2006","journal-title":"Clin. Biochem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"9148","DOI":"10.1021\/ja953505b","article-title":"Accelerated racemization of aspartic acid and asparagine residues via succinimide intermediates:\u2009 An ab initio theoretical exploration of mechanism","volume":"118","author":"Radkiewicz","year":"1996","journal-title":"J. Am. Chem. Soc."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1159\/000212218","article-title":"Considerations on the role of aspartic acid racemization in the aging process","volume":"23","author":"Helfman","year":"1977","journal-title":"Gerontology"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Takahashi, O., Kirikoshi, R., and Manabe, N. (2016). Academic editor Mihai V. Putz. Racemization of the succinimide intermediate formed in proteins and peptides: A computational study of the mechanism catalyzed by dihydrogen phosphate ion. Int. J. Mol. Sci., 10.","DOI":"10.3390\/ijms17101698"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1093\/jnen\/62.3.248","article-title":"Beta-amyloid racemized at the Ser26 residue in the brains of patients with Alzheimer\u2019s disease: Implications in the pathogenesis of Alzheimer\u2019s disease","volume":"62","author":"Kubo","year":"2003","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e561","DOI":"10.1038\/tp.2015.52","article-title":"D-serine levels in Alzheimer\u2019s disease: Implications for novel biomarker development","volume":"5","author":"Madeira","year":"2015","journal-title":"Transl. Psychiatry"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/S0047-6374(01)00363-3","article-title":"Racemization of aspartic acid in human proteins","volume":"1","author":"Collins","year":"2002","journal-title":"Ageing Res. Rev."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3072","DOI":"10.1016\/S0021-9258(18)53661-9","article-title":"Structural alterations in the peptide backbone of \u03b2-amyloid core protein may account for its deposition and stability in Alzheimer\u2019s disease","volume":"268","author":"Roher","year":"1993","journal-title":"J. Biol. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/S0925-4439(98)00014-3","article-title":"Irreversible dimerization\/tetramerization and post-translational modifications inhibit proteolytic degradation of A\u03b2 peptides of Alzheimer\u2019s disease","volume":"1406","author":"Kuo","year":"1998","journal-title":"Biochim. Biophys. Acta."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"803","DOI":"10.18632\/aging.100362","article-title":"Phosphorylation of amyloid beta (A\u03b2) peptides\u2014A trigger for formation of toxic aggregates in Alzheimer\u2019s disease","volume":"3","author":"Kumar","year":"2011","journal-title":"Aging"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1111\/j.1432-1033.1994.t01-1-00917.x","article-title":"Aspartate-bond isomerization affects the major conformations of synthetic peptides","volume":"226","author":"Szendrei","year":"1994","journal-title":"Eur. J. Biochem. FEBS"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1038\/nsmb.2991","article-title":"A\u03b2 (1\u201342) fibril structure illuminates self-recognition and replication of amyloid in Alzheimer\u2019s disease","volume":"22","author":"Xiao","year":"2015","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"9520","DOI":"10.1038\/s41598-017-10422-x","article-title":"Diversity of amyloid-beta proteoforms in the Alzheimer\u2019s disease brain","volume":"7","author":"Wildburger","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Jiang, N., Leithold, L.H.E., Post, J., Ziehm, T., Mauler, J., Gremer, L., Cremer, M., Schartmann, E., Shah, N.J., and Kutzsche, J. (2015). Preclinical pharmacokinetic studies of the tritium labelled D-enantiomeric peptide D3 developed for the treatment of Alzheimer\u2019s disease. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0128553"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"7762","DOI":"10.1039\/C8CC03235A","article-title":"Chiral modulation of amyloid beta fibrillation and cytotoxicity by enantiomeric carbon dots","volume":"54","author":"Malishev","year":"2018","journal-title":"Chem. Commun."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"150","DOI":"10.15698\/cst2018.07.143","article-title":"Alzheimer\u2019s disease: Amyloid-based pathogenesis and potential therapies","volume":"2","author":"Zhou","year":"2018","journal-title":"Cell Stress."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"33958","DOI":"10.1039\/C4RA04694C","article-title":"Unusual post-translational protein modifications: The benefits of sophistication","volume":"4","author":"Ravikirana","year":"2014","journal-title":"RSC Adv."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"6192","DOI":"10.3748\/wjg.v22.i27.6192","article-title":"Aberrant post-translational protein modifications in the pathogenesis of alcohol-induced liver injury","volume":"22","author":"Osna","year":"2016","journal-title":"World J. Gastroenterol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"6021","DOI":"10.1073\/pnas.0501823102","article-title":"Implications of the serine protease HtrA1 in amyloid precursor protein processing","volume":"102","author":"Grau","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Gieldon, A., Zurawa-Janicka, D., Jarzab, M., Wenta, T., Golik, P., Dubin, G., Lipinska, B., and Ciarkowski, J. (2016). Distinct 3D architecture and dynamics of the human Htra2(Omi) protease and its mutated variants. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0161526"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"746","DOI":"10.2174\/1389203717666160311115750","article-title":"Pathogenic role of serine protease HtrA2\/Omi in neurodegenerative diseases","volume":"18","author":"Goo","year":"2017","journal-title":"Curr. Protein Pept. Sci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.jtherbio.2017.06.004","article-title":"The small heat shock protein Hsp27: Present understanding and future prospects","volume":"69","author":"Singh","year":"2017","journal-title":"J. Therm. Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"794","DOI":"10.1016\/S0021-9258(18)48354-8","article-title":"Human HSP27 is phosphorylated at serines 78 and 82 by heat shock and mitogen-activated kinases that recognize the same amino acid motif as S6 kinase II","volume":"267","author":"Landry","year":"1992","journal-title":"J. Biol. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Katsogiannou, M., Andrieu, C., and Rocchi, P. (2014). Heat shock protein 27 phosphorylation state is associated with cancer progression. Front. Genet.","DOI":"10.3389\/fgene.2014.00346"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/S0076-6879(99)09009-6","article-title":"Chemical modifications of deposited amyloid-\u03b2 peptides","volume":"309","author":"Lowenson","year":"1999","journal-title":"Methods Enzym."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Takahashi, O., Kirikoshi, R., and Manabe, N. (2017). Racemization of serine residues catalyzed by dihydrogen phosphate Ion: A computational Study. Catalysts, 7.","DOI":"10.3390\/catal7120363"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1111\/j.1471-4159.1988.tb13231.x","article-title":"Neuritic plaque amyloid in Alzheimer\u2019s disease is highly racemized","volume":"50","author":"Shapira","year":"1988","journal-title":"J. Neurochem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1016\/S0306-4522(01)00155-5","article-title":"Drastic neuronal loss in vivo by beta-amyloid racemized at Ser (26) residue: Conversion of non-toxic [D-Ser (26)] beta-amyloid 1\u201340 to toxic and proteinase-resistant fragments","volume":"104","author":"Kaneko","year":"2001","journal-title":"Neuroscience"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"10205","DOI":"10.1016\/S0021-9258(17)34045-0","article-title":"Racemization of Asp23 residue affects the aggregation properties of Alzheimer amyloid beta protein analogues","volume":"269","author":"Tomiyama","year":"1994","journal-title":"J. Biol. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1002\/jnr.10350","article-title":"Iso-aspartate formation at position 23 of amyloid beta peptide enhanced fibril formation and deposited onto senile plaques and vascular amyloids in Alzheimer\u2019s disease","volume":"70","author":"Shimizu","year":"2002","journal-title":"J. Neurosci. Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3357","DOI":"10.1038\/s41467-019-11183-z","article-title":"Structure of A-\u03b2 (20\u201334) with Alzheimer\u2019s-associated isomerization at Asp23 reveals a distinct protofilament interface","volume":"10","author":"Warmack","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"8641","DOI":"10.1074\/jbc.M111.279133","article-title":"Phosphorylation of amyloid-\u03b2 peptide at serine-8 attenuates its clearance via insulin-degrading and angiotensin-converting enzymes","volume":"287","author":"Kumar","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"302","DOI":"10.3389\/fnmol.2018.00302","article-title":"Phosphorylation of the amyloid-beta peptide inhibits zinc-dependent aggregation, prevents Na,K-ATPase inhibition, and reduces cerebral plaque deposition","volume":"11","author":"Barykin","year":"2018","journal-title":"Front. Mol. Neurosci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"11359","DOI":"10.1038\/ncomms11359","article-title":"Phosphorylation modifies the molecular stability of \u03b2-amyloid deposits","volume":"7","author":"Amininasab","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3839","DOI":"10.1097\/00001756-200112040-00047","article-title":"Phosphorylation of amyloid-beta at the serine 26 residue by human cdc2 kinase","volume":"12","author":"Milton","year":"2001","journal-title":"Neuroreport"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1007\/s00401-016-1546-0","article-title":"Phosphorylation of the amyloid \u03b2-peptide at Ser26 stabilizes oligomeric assembly and increases neurotoxicity","volume":"131","author":"Kumar","year":"2016","journal-title":"Acta Neuropathol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1021\/tx500353s","article-title":"Nitration of Y10 in A\u03b21\u201340: Is it a compensatory reaction against oxidative\/nitrative stress and A\u03b2 aggregation?","volume":"28","author":"Zhao","year":"2015","journal-title":"Chem. Res. Toxicol."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Rib\u00f3, J.M., and Hochberg, D. (2019). Concept Paper. Chemical basis of biological homochirality during the abiotic evolution stages on Earth. Symmetry, 11.","DOI":"10.3390\/sym11060814"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1620\/tjem.174.251","article-title":"Racemization: Its biological significance on neuropathogenesis of Alzheimer\u2019s disease","volume":"174","author":"Mori","year":"1994","journal-title":"Tohoku J. Exp. Med."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"472","DOI":"10.3389\/fchem.2019.00472","article-title":"Three decades of amyloid beta synthesis: Challenges and advances","volume":"7","author":"Kasim","year":"2019","journal-title":"Front. Chem."},{"key":"ref_47","unstructured":"Dyakin, V.V., and Lucas, J. (2017, January 16\u201320). Non-equilibrium phase transition in biochemical\u2014Systems. Chain of chirality transfer as Determinant of Brain Functional Laterality. Relevance to Alzheimer disease and cognitive psychology. Proceedings of the Alzheimer\u2019s Association International Conference (AAIC-2017), London, UK."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1073\/pnas.1620001114","article-title":"Core concept: How nonequilibrium thermodynamics speaks to the mystery of life","volume":"114","author":"Ornes","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_49","unstructured":"Schr\u00f6dinger, E. (1994). What is Life? The Physical Aspect of the Living Cell, Cambridge University Press."},{"key":"ref_50","unstructured":"Zucchi, C., Caglioti, L., and Palyi, G. (1999). The role of homochirality in evolution. Advances in BioChirality, Elsevier Science."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2304","DOI":"10.1016\/j.bpj.2019.05.013","article-title":"Protein glycation by glyoxal promotes amyloid formation by Islet Amyloid polypeptide","volume":"116","author":"Hsu","year":"2019","journal-title":"Biophys. J."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1016\/j.bpj.2008.10.022","article-title":"Structural differences between A\u03b2 (1\u201340) intermediate oligomers and fibrils elucidated by proteolytic fragmentation and hydrogen\/deuterium exchange","volume":"96","author":"Zhang","year":"2009","journal-title":"Biophys. J."}],"container-title":["Symmetry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-8994\/12\/4\/585\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:16:23Z","timestamp":1760174183000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-8994\/12\/4\/585"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,4,7]]},"references-count":52,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2020,4]]}},"alternative-id":["sym12040585"],"URL":"https:\/\/doi.org\/10.3390\/sym12040585","relation":{},"ISSN":["2073-8994"],"issn-type":[{"type":"electronic","value":"2073-8994"}],"subject":[],"published":{"date-parts":[[2020,4,7]]}}}