{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nALDH4A1 is a multifunctional mitochondrial dehydrogenase with a dual role in amino acid metabolism and cardiovascular pathology. Functionally, it catalyzes the NAD⁺‐dependent oxidation of γ-glutamate semialdehyde to L-glutamate in proline catabolism and converts 4-hydroxy-L-glutamate-γ-semialdehyde into downstream metabolites during hydroxyproline degradation. In the setting of cardiovascular disease, ALDH4A1 has been implicated as a novel autoantigen, with altered tissue distribution and increased circulating levels correlating with atherosclerotic plaque development. Notably, the infusion of antibodies against ALDH4A1 in experimental models delays plaque formation and reduces circulating lipid levels, underscoring its potential as both a biomarker and a therapeutic target."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "Dissecting its biochemical properties, structural studies have illuminated how ALDH4A1 accommodates its substrates. High-resolution crystal structures reveal that efficient catalysis requires substrates with sufficient carbon chain length to bridge the distance between an anchor loop and an oxyanion hole within the active site. These detailed analyses have established the parameters for substrate binding and inhibition, thereby clarifying the structure–activity relationships essential for its enzymatic role."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "Further kinetic and crystallographic examinations have emphasized ALDH4A1’s dual specificity. Investigations comparing the stereoisomers of proline and hydroxyproline have shown that trans-4-hydroxy-L-proline, for example, acts as a potent competitive inhibitor. This stereochemical selectivity and the impact of substrate inhibition not only provide deeper insights into its catalytic mechanism but also highlight avenues for potential pharmacological modulation, with implications for managing metabolic disturbances that underlie cardiovascular disease."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Cristina Lorenzo, Pilar Delgado, Christian E Busse, et al. "}, {"type": "b", "children": [{"type": "t", "text": "ALDH4A1 is an atherosclerosis auto-antigen targeted by protective antibodies."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nature (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41586-020-2993-2"}], "href": "https://doi.org/10.1038/s41586-020-2993-2"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33268892"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33268892"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Jiannan Li, Runzhen Chen, Jinying Zhou, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Atherosclerotic Autoantigen ALDH4A1 as a Novel Immunological Indicator for Plaque Erosion in Patients with ST Segment Elevated Myocardial Infarction."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Thromb Haemost (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1055/s-0043-1777265"}], "href": "https://doi.org/10.1055/s-0043-1777265"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38109905"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38109905"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Travis A Pemberton, John J Tanner "}, {"type": "b", "children": [{"type": "t", "text": "Structural basis of substrate selectivity of Δ(1)-pyrroline-5-carboxylate dehydrogenase (ALDH4A1): semialdehyde chain length."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Arch Biochem Biophys (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.abb.2013.07.024"}], "href": "https://doi.org/10.1016/j.abb.2013.07.024"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23928095"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23928095"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Alexandra N Bogner, Kyle M Stiers, Cole M McKay, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Structural basis for the stereospecific inhibition of the dual proline/hydroxyproline catabolic enzyme ALDH4A1 by trans-4-hydroxy-L-proline."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Protein Sci (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/pro.4131"}], "href": "https://doi.org/10.1002/pro.4131"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34048122"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34048122"}]}]}]}