Definition and research guide
This page combines a MeSH definition, publication statistics and selected research abstracts. It is a starting point for reading the literature, not a medical textbook or a systematic evidence review.
Content available: 3 complete abstracts (567 words), 9 references. Full article text is not stored or reproduced here; follow the PMID, DOI or PMC links to read the original sources and their access terms.
Definition
A characteristic feature of enzyme activity in relation to the kind of substrate on which the enzyme or catalytic molecule reacts.
Definition: NLM Medical Subject Headings (MeSH) scope note (Public domain (U.S. National Library of Medicine); attribution requested). View the MeSH record.
Also known as: Specificities, Substrate; Specificity, Substrate; Substrate Specificities.
Where it fits in the MeSH classification
- Broader topics
- Biochemical Phenomena
Research landscape
PubMed indexes 103,969 records tagged with the MeSH heading “Substrate Specificity” (counts retrieved 2026-10-29). 8,128 of them (7.8%) were published from 2020 onward, and the busiest period so far is through 1999 with 38,402 records.
Reviews account for 6,895 records (6.6%) and meta-analyses for 11. Randomized controlled trials number 63 (0.1%) as a share of all records on the topic. Randomized trials make up only a small share of this literature, so much of what is known comes from laboratory, observational or descriptive work.
Show the data
| Period | Records |
|---|---|
| through 1999 | 38,402 |
| 2000-2009 | 31,596 |
| 2010-2019 | 25,843 |
| 2020 onward | 8,128 |
Publication-type chart data
| Type | Records | Share |
|---|---|---|
| Reviews | 6,895 | 6.6% |
| Meta-analyses | 11 | 0.0% |
| Randomized controlled trials | 63 | 0.1% |
Method: PubMed query "Substrate Specificity"[MeSH Terms] with publication-type and date filters, retrieved 2026-10-29.
Reading the evidence in molecular biology
Molecular biology establishes mechanisms through controlled experiments, often in simplified systems such as purified proteins, cultured cells or model organisms. Such work can show what is possible in a defined system, but whether a pathway matters in a whole organism or in human disease needs further evidence. Check the experimental system, whether findings were reproduced by independent groups, and whether the authors tested the mechanism directly or inferred it from correlation.
Evidence from open-access studies
These open-access studies come from PubMed’s best-match results for this heading (papers whose main topic it is), ranked here by citation count, with one recent addition. Each abstract is reproduced in full under its recorded open licence so that you can read the authors’ own words. They illustrate the literature; they are not a systematic summary of it. Citation counts measure attention, not reliability or clinical benefit.
| Study / authors | Year | Source label / design | Europe PMC citations | Licence / source |
|---|---|---|---|---|
| The intrinsic substrate specificity of the human tyrosine kinome | 2024 | Research article Design not recorded in structured metadata | 182 | cc by PMID 38720073 · DOI · PMC11136658 |
| Targeted protein degradation via intramolecular bivalent glues | 2024 | Research article Design not recorded in structured metadata | 168 | cc by PMID 38383787 · DOI · PMC10917667 |
| Sequence-specific intramembrane proteolysis: identification of a recognition motif in rhomboid substrates | 2009 | Research article Design not recorded in structured metadata | 166 | cc by PMID 20064469 · DOI · PMC2941825 |
The intrinsic substrate specificity of the human tyrosine kinome [1]
Abstract reading summary — source excerpts
- Opening excerpt
- Phosphorylation of proteins on tyrosine (Tyr) residues evolved in metazoan organisms as a mechanism of coordinating tissue growth1.
- Closing excerpt
- Finally we show that the intrinsic substrate specificity of Tyr kinases has remained fundamentally unchanged from worms to humans, suggesting that the fidelity between Tyr kinases and their protein substrate sequences has been maintained across hundreds of millions of years of evolution.
- Interpretation limits
- Verbatim excerpts from the authors’ abstract; the closing excerpt may describe a finding, limitation or recommendation. Design, population, effect size and uncertainty have not been independently extracted or appraised. Read the complete abstract and linked paper before interpreting the findings.
Read complete abstract (230 words)
Phosphorylation of proteins on tyrosine (Tyr) residues evolved in metazoan organisms as a mechanism of coordinating tissue growth1. Multicellular eukaryotes typically have more than 50 distinct protein Tyr kinases that catalyse the phosphorylation of thousands of Tyr residues throughout the proteome1-3. How a given Tyr kinase can phosphorylate a specific subset of proteins at unique Tyr sites is only partially understood4-7. Here we used combinatorial peptide arrays to profile the substrate sequence specificity of all human Tyr kinases. Globally, the Tyr kinases demonstrate considerable diversity in optimal patterns of residues surrounding the site of phosphorylation, revealing the functional organization of the human Tyr kinome by substrate motif preference. Using this information, Tyr kinases that are most compatible with phosphorylating any Tyr site can be identified. Analysis of mass spectrometry phosphoproteomic datasets using this compendium of kinase specificities accurately identifies specific Tyr kinases that are dysregulated in cells after stimulation with growth factors, treatment with anti-cancer drugs or expression of oncogenic variants. Furthermore, the topology of known Tyr signalling networks naturally emerged from a comparison of the sequence specificities of the Tyr kinases and the SH2 phosphotyrosine (pTyr)-binding domains. Finally we show that the intrinsic substrate specificity of Tyr kinases has remained fundamentally unchanged from worms to humans, suggesting that the fidelity between Tyr kinases and their protein substrate sequences has been maintained across hundreds of millions of years of evolution.
Abstract reproduced from the open-access article under the recorded cc by licence; © the authors. PMID 38720073 · DOI · PMC11136658
Targeted protein degradation via intramolecular bivalent glues [2]
Abstract reading summary — source excerpts
- Opening excerpt
- Targeted protein degradation is a pharmacological modality that is based on the induced proximity of an E3 ubiquitin ligase and a target protein to promote target ubiquitination and proteasomal degradation.
- Closing excerpt
- We thus introduce a new modality in targeted protein degradation, which works by bridging protein domains in cis to enhance surface complementarity with E3 ligases for productive ubiquitination and degradation.
- Interpretation limits
- Verbatim excerpts from the authors’ abstract; the closing excerpt may describe a finding, limitation or recommendation. Design, population, effect size and uncertainty have not been independently extracted or appraised. Read the complete abstract and linked paper before interpreting the findings.
Read complete abstract (198 words)
Targeted protein degradation is a pharmacological modality that is based on the induced proximity of an E3 ubiquitin ligase and a target protein to promote target ubiquitination and proteasomal degradation. This has been achieved either via proteolysis-targeting chimeras (PROTACs)-bifunctional compounds composed of two separate moieties that individually bind the target and E3 ligase, or via molecular glues that monovalently bind either the ligase or the target1-4. Here, using orthogonal genetic screening, biophysical characterization and structural reconstitution, we investigate the mechanism of action of bifunctional degraders of BRD2 and BRD4, termed intramolecular bivalent glues (IBGs), and find that instead of connecting target and ligase in trans as PROTACs do, they simultaneously engage and connect two adjacent domains of the target protein in cis. This conformational change 'glues' BRD4 to the E3 ligases DCAF11 or DCAF16, leveraging intrinsic target-ligase affinities that do not translate to BRD4 degradation in the absence of compound. Structural insights into the ternary BRD4-IBG1-DCAF16 complex guided the rational design of improved degraders of low picomolar potency. We thus introduce a new modality in targeted protein degradation, which works by bridging protein domains in cis to enhance surface complementarity with E3 ligases for productive ubiquitination and degradation.
Abstract reproduced from the open-access article under the recorded cc by licence; © the authors. PMID 38383787 · DOI · PMC10917667
Sequence-specific intramembrane proteolysis: identification of a recognition motif in rhomboid substrates [3]
Abstract reading summary — source excerpts
- Opening excerpt
- Members of the widespread rhomboid family of intramembrane proteases cleave transmembrane domain (TMD) proteins to regulate processes as diverse as EGF receptor signaling, mitochondrial dynamics, and invasion by apicomplexan parasites.
- Closing excerpt
- Our work demonstrates that intramembrane proteases can be sequence specific and that genome-wide substrate prediction based on their recognition motifs is feasible.
- Interpretation limits
- Verbatim excerpts from the authors’ abstract; the closing excerpt may describe a finding, limitation or recommendation. Design, population, effect size and uncertainty have not been independently extracted or appraised. Read the complete abstract and linked paper before interpreting the findings.
Read complete abstract (139 words)
Members of the widespread rhomboid family of intramembrane proteases cleave transmembrane domain (TMD) proteins to regulate processes as diverse as EGF receptor signaling, mitochondrial dynamics, and invasion by apicomplexan parasites. However, lack of information about their substrates means that the biological role of most rhomboids remains obscure. Knowledge of how rhomboids recognize their substrates would illuminate their mechanism and might also allow substrate prediction. Previous work has suggested that rhomboid substrates are specified by helical instability in their TMD. Here we demonstrate that rhomboids instead primarily recognize a specific sequence surrounding the cleavage site. This recognition motif is necessary for substrate cleavage, it determines the cleavage site, and it is more strictly required than TM helix-destabilizing residues. Our work demonstrates that intramembrane proteases can be sequence specific and that genome-wide substrate prediction based on their recognition motifs is feasible.
Abstract reproduced from the open-access article under the recorded cc by licence; © the authors. PMID 20064469 · DOI · PMC2941825
Key reviews and meta-analyses
The most cited review-type papers among PubMed’s best-match results for this heading, listed with bibliographic details only. Follow the links for the full text and access terms.
- Research article Enzyme promiscuity: mechanism and applications [4]
- Research article Caspase substrates [5]
- Research article Substrate specificity of protein kinases and computational prediction of substrates [6]
- Research article Substrate recognition by nonribosomal peptide synthetase multi-enzymes [7]
- Research article Molecular basis of substrate specificity in family 1 glycoside hydrolases [8]
- Research article Structural biology of the aldo-keto reductase family of enzymes: catalysis and cofactor binding [9]
References
- Yaron-Barir TM, Joughin BA, Huntsman EM, Kerelsky A, Cizin DM, Cohen BM, et al.. The intrinsic substrate specificity of the human tyrosine kinome. . 2024. PMID 38720073 · DOI · PMC11136658
- Hsia O, Hinterndorfer M, Cowan AD, Iso K, Ishida T, Sundaramoorthy R, et al.. Targeted protein degradation via intramolecular bivalent glues. . 2024. PMID 38383787 · DOI · PMC10917667
- Strisovsky K, Sharpe HJ, Freeman M. Sequence-specific intramembrane proteolysis: identification of a recognition motif in rhomboid substrates. . 2009. PMID 20064469 · DOI · PMC2941825
- Hult K, Berglund P. Enzyme promiscuity: mechanism and applications. Trends Biotechnol. 2007. PMID 17379338 · DOI
- Timmer JC, Salvesen GS. Caspase substrates. Cell Death Differ. 2007. PMID 17082814 · DOI
- Kobe B, Kampmann T, Forwood JK, Listwan P, Brinkworth RI. Substrate specificity of protein kinases and computational prediction of substrates. Biochim Biophys Acta. 2005. PMID 16172032 · DOI
- Lautru S, Challis GL. Substrate recognition by nonribosomal peptide synthetase multi-enzymes. Microbiology (Reading). 2004. PMID 15184549 · DOI
- Marana SR. Molecular basis of substrate specificity in family 1 glycoside hydrolases. IUBMB Life. 2006. PMID 16611572 · DOI
- Sanli G, Dudley JI, Blaber M. Structural biology of the aldo-keto reductase family of enzymes: catalysis and cofactor binding. Cell Biochem Biophys. 2003. PMID 12663943 · DOI
About this article
- Sources
- NLM Medical Subject Headings (definition, synonyms); NCBI PubMed (counts, identifiers); Europe PMC (open-access abstracts and citation counts).
- Verification
- Every reference was resolved against PubMed on 2026-10-31; title, year and DOI matched.
- Review state
- automated source verified; no human expert review has been recorded yet.
- Version
- 1, last updated 2026-10-29.
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Evidence strength
EvidenceHelix's computed view of the study designs behind this topic: how common meta-analyses, randomized trials and reviews are, how recent the literature is, and a plain-language reading. It describes the design mix of the literature. It is not a quality appraisal of any study, and it is not medical advice.