Biology subjects

Mikhael, P.

Publications and source records attributed to Mikhael, P..

3 recordsLinked to original sources

bioRxiv2024

Chemical codes promote selective compartmentalization of proteins

Cells have evolved mechanisms to distribute [~]10 billion protein molecules to subcellular compartments where diverse proteins involved in shared functions must efficiently assemble. Here, we demonstrate that proteins with shared functions share amino acid sequence codes that guide them to compartment destinations. A protein language model, ProtGPS, was developed that predicts with high performance the compartment localization of human proteins excluded from the training set. ProtGPS successfully guided generation of novel protein sequences that selectively assemble in targeted subcellular compartments. ProtGPS also identified pathological mutations that change this code and lead to altered subcellular localization of proteins. Our results indicate that protein sequences contain not only a folding code, but also a previously unrecognized code governing their distribution in specific cellular compartments.

biochemistry↗

bioRxiv2019

Dietary methionine restriction targets one carbon metabolism in humans and produces broad therapeutic responses in cancer

Nutrition exerts profound effects on health and dietary interventions are commonly used to treat diseases of metabolic etiology. Although cancer has a substantial metabolic component, the principles that define whether nutrition may be used to influence tumour outcome are unclear. Nevertheless, it is established that targeting metabolic pathways with pharmacological agents or radiation can sometimes lead to controlled therapeutic outcomes. In contrast, whether specific dietary interventions could influence the metabolic pathways that are targeted in standard cancer therapies is not known. We now show that dietary restriction of methionine (MR), an essential amino acid, and the reduction of which has aging and obesogenic properties, influences cancer outcome through controlled and reproducible changes to one carbon metabolism. This pathway metabolizes methionine and further is the target of a host of cancer interventions involving chemotherapy and radiation. MR produced therapeutic responses in chemoresistant RAS-driven colorectal cancer patient derived xenografts and autochthonous KRASG12D+/-;TP53-/- -driven soft tissue sarcomas resistant to radiation. Metabolomics revealed the therapeutic mechanisms to occur through tumor cell autonomous effects on the flux through one carbon metabolism that impacted redox and nucleotide metabolism, thus interacting with the antimetabolite or radiation intervention. Finally, in a controlled and tolerated feeding study in humans, MR resulted in similar effects on systemic metabolism as obtained in responsive mice. These findings provide evidence that a targeted dietary manipulation can affect specific tumor cell metabolism to mediate broad aspects of cancer outcome.

cancer biology↗

bioRxiv2018

Environmental factors shape methionine metabolism in p16/MTAP deleted cells

The co-deletion of a common tumor suppressor locus and neighboring metabolic gene is an attractive possible synthetic dependency of tumor suppression on metabolism. However, the general impact that these co-deletions have on metabolism, which also dependent on nutrient availability and the tissue of origin, is unknown. As a model to investigate this question, we considered a set of tissue-matched cancer cells with homozygous co-deletions in CDKN2a and MTAP, genes respectively encoding the most commonly deleted tumor suppressor p16 and an enzyme involved in methionine metabolism. A comparative metabolomics analysis revealed that while there exists a definite pan-cancer metabolic signature of MTAP-deletion, this signature was not preserved when cells were subjected to changes in the availability of methionine, serine, or cysteine, nutrients related to methionine metabolism. Notably, the heterogeneity exhibited by these cells in their responsiveness to nutrient availability dominated both MTAP status and tissue-of-origin. Furthermore, re-expression of MTAP exerted a modest effect on metabolism. Together these findings demonstrate that environmental factors, particularly nutrition and tissue identity, may overwhelm the genetic effects of collateral deletions of metabolic genes.

molecular biology↗