Biology subjects

Paramasivam, S.

Publications and source records attributed to Paramasivam, S..

5 recordsLinked to original sources

bioRxiv2026

One lysine, two acyl marks: 2-hydroxyisobutyrylation and acetylation of G6PD differ in outcome and regulation

Lysine 2-hydroxyisobutyrylation is a widespread post-translational modification enriched in enzymes of central carbon metabolism, yet its site-specific biochemical consequences remain poorly defined and usually inferred from amino acid substitutions or heterogeneously modified protein preparations. Using genetic code expansion technology, we generated homogeneous human glucose-6-phosphate dehydrogenase (G6PD) carrying an authentic 2-hydroxyisobutyryl group at nine individual lysine residues. 2-hydroxyisobutyrylation affected G6PD activity in a strongly site-dependent manner: modification within or adjacent to the catalytic pocket (K171, K205, K360), or at the tetramer interface (K288), abolished activity, whereas modification of K386, near the structural NADP+ binding site, reduced catalytic efficiency and destabilized the enzyme. HibK386 G6PD was less oligomeric, while inactive HibK288 G6PD formed stable oligomers, suggesting that in HibK288 G6PD, assembly and catalysis are separable. Molecular dynamics simulations indicated that 2-hydroxyisobutyrylation of K386 reorients the side chain toward the solvent and weakens hydrogen bonding and salt-bridge across the tetramer interface. K386 is also subject to acetylation, allowing the comparison between two acyl groups at one residue; acetylation destabilized G6PD without substantially impairing catalysis, whereas 2-hydroxyisobutyrylation did both, and the two marks were differentially recognized by their erasers. SIRT2 removed both and restored the activity of the purified enzyme, whereas SIRT1 readily deacetylated AcK386 but was a poor de-2-hydroxyisobutyrylase of this position. SIRT2 also de-2-hydroxyisobutyrylated HibK288 G6PD and PKM2 HibK62, but not PKM2 HibK115 or HibK305. Together, these findings identify site-specific 2-hydroxyisobutyrylation as a potent inhibitory modification of G6PD, demonstrate that chemically distinct acylations at the same site can exert different functional effects, and establish deacylase specificity as a function of both modification chemistry and residue context.

biochemistry↗

bioRxiv2026

HDAC6 and SSAT2 orchestrate acetyllysine metabolism and protein homeostasis

Lysine acetylation is a prevalent and dynamic posttranslational modification, yet the metabolic fate and physiological role of free N {varepsilon}-acetyl-L-lysine (AcK) remain unclear. Here, we identify opposing enzyme-catalyzed reactions linking lysine/AcK homeostasis to protein stability. We show that the first catalytic domain of HDAC6 stereospecifically deacetylates free AcK, establishing HDAC6 as an N {varepsilon}-acyl-lysine deacylase. AcK functions both as a recyclable lysine reservoir and as a signaling metabolite that elevates -tubulin acetylation and suppresses cell migration. Conversely, SSAT2 acetylates free lysine in cells and undergoes substrate-dependent C-terminal autoacetylation. We demonstrate that C-terminal lysine acetylation constitutes a reversible proteasomal degradation signal that promotes SSAT2 degradation and may extend to additional proteins bearing a terminal lysine. Stabilization of SSAT2 by HDAC6-dependent deacetylation, together with intricate regulation affected by substrate availability, reveals a novel mechanism that couples amino acid recycling to cytoskeletal dynamics and proteostasis.

biochemistry↗

bioRxiv2024

History of recurrent short and long-term coral bleaching events in Indian coral reefs: a a systematic review of contrasting bleaching patterns, lessons learned, and future directions

Climate change has intensified coral bleaching events, leading to widespread coral mortality and threatening the coral reef survival worldwide. However, species susceptibility patterns to bleaching differ spatially and temporally, making it crucial to understand bleaching impact and species susceptibility patterns across latitudinal ranges, particularly from understudied locations. We critically reviewed 23 years of bleaching episodes on Indian coral reefs (four major reefs and other patch reefs) reported from 1998 to 2020 to understand the geographical footprint of bleaching patterns, species susceptibility differences, and their impact. We found that all four major Indian reef systems (Gulf of Kachchh, Gulf of Mannar, Lakshadweep, and the Andaman Islands) have experienced three major bleaching episodes (1998, 2010, and 2016) and multiple short-term bleaching events. Short-term bleaching events (DHWs> four weeks) created differences in species susceptibility, but the disparity among species diminished to long-term bleaching events (DHWs <4 weeks) in all reef sites. Acropora, Porites, Pocillopora, Montipora, and Turninaria in the Gulf of Mannar, Porites, and Favia in the Gulf of Kachchh, and Acropora in the Andaman and Lakshadweep were the most vulnerable genera during all the bleaching events. In terms of recovery, Porites and other massive forms recovered better than branching forms. Furthermore, species susceptibility pattern analysis (winners vs. losers) to 2016 long-term bleaching events found conflicting results from studies (one-time surveys) in the same area. This result indicates that a one-time survey (survey timing) influences results as bleaching events lengthen, necessitating repeated surveys to determine winners and losers. Although inconsistent data from different study sites makes it difficult to create predictive models, data collected over the past 23 years provides critical insight into coral community susceptibility patterns and bleaching impacts, underscoring the need for systematic, uniform surveys in the future.

ecology↗

bioRxiv2022

Phosphoproteomic mapping reveals distinct signaling actions and activation of protein synthesis and muscle hypertrophy by Isthmin-1

The secreted protein Isthmin-1 (Ism1) mitigates diabetes by increasing adipocyte and skeletal muscle glucose uptake by activating the PI3K-Akt pathway. However, while both Ism1 and insulin converge on these common targets, Ism1 has distinct cellular actions suggesting divergence in downstream intracellular signaling pathways. To understand the biological complexity of Ism1 signaling, we performed phosphoproteomic analysis after acute exposure, revealing overlapping and distinct pathways of Ism1 and insulin. We identify a 53 % overlap between Ism1 and insulin signaling and Ism1-mediated phosphoproteome-wide alterations in [~] 450 proteins that are not shared with insulin. Interestingly, we find several unknown phosphorylation sites on proteins related to protein translation, mTOR pathway and, unexpectedly, muscle function in the Ism1 signaling network. Physiologically, Ism1 ablation in mice results in altered proteostasis, including lower muscle protein levels under fed and fasted conditions, reduced amino acid incorporation into proteins, and reduced phosphorylation of the key protein synthesis effectors Akt and downstream mTORC1 targets. As metabolic disorders such as diabetes are associated with accelerated loss of skeletal muscle protein content, these studies define a non-canonical mechanism by which this anti-diabetic circulating protein controls muscle biology.

cell biology↗

bioRxiv2022

In silico identification of novel peptides as potential modulators of Aβ42 Amyloidogenesis

Alzheimers Disease is a neurodegenerative disease for which no cure is available at present. The presence of amyloid plaques in the extracellular space of neural cells is the key feature of this fatal disease. Amyloid-Beta (A{beta}) is a 40-42 amino acid peptide and the main component of amyloid plaques. This peptide is produced by the proteolysis of Amyloid Precursor Protein by presenilin. Deposition of 42 residual A{beta} peptides forms fibrils structure, leading to disruption of neuron synaptic transmission, inducing neural cell toxicity, ultimately leading to neuron death. To modulate the amyloidosis of A{beta} peptides, various novel peptides have been investigated via molecular docking and molecular dynamic simulation studies. The sequence-based peptides were designed and investigated for their interaction with A{beta}42 monomer and fibril using the molecular docking method, and their influence on the structural stability of target proteins was studied using molecular simulations. According to the docking results, amongst all the synthetic peptides, the peptide YRIGY (P6) has the highest binding affinity with A{beta}42 fibril, and the peptide DKAPFF (P12) shows better binding with A{beta}42 monomer. Moreover, simulation results also suggest that the higher the binding affinity, the better the inhibitory action. From these findings, it is suggested that both the peptides can modulate the amyloidogenesis, but peptide (P6) has better potential for the disaggregation of the fibrils, whereas peptide P12 stabilizes the native structure of the A{beta}42 monomer more effectively and hence can serve as a potential amyloid inhibitor. Thus, these peptides can be explored as therapeutic agents against Alzheimers Disease.

bioinformatics↗