Methanethiol: The Scent of Disease and Discovery

In a previous blog post, we discussed the role of SELENBP1 in nonosyndromic (monosymptomatic) halitosis. We learned that if this enzyme isn't functioning correctly, it can lead to the release of more Methanethiol, a volatile and rather unpleasant-smelling gas often associated with the aroma of rotten cabbage. 

However, Selenium binding protein 1 (SELENBP1) isn't just a casual bystander in our biological processes. It has been linked to various health conditions and diseases. These include:

Hypermethioninemia: A rare condition that can sometimes come with learning disabilities and neurological issues.

Schizophrenia: a complex mental disorder that challenges our understanding of the human mind

Hypertension and Ischemic Heart Conditions, conditions such as Guillain-Barré syndrome and Infectious Diseases: Dysregulation of SELENBP1 is associated with Zika virus (ZIKV) and dengue infections, as well as COVID-19.

SELENBP1's role in several types of cancer, including its downregulation at the onset of cancer and upregulation in later stages, is a subject of intense research.

Methanethiol contributes to the distinct scent signature linked to cancer, characterized by a combination of volatile organic compounds (VOCs). Researchers are increasingly exploring this intriguing scent profile as a potential tool for non-invasive early cancer diagnosis.

Methanethiol is a testament to the intricate connections between genetics, metabolism, and disease, reminding us that even the smelliest molecules can lead to groundbreaking discoveries.

Methanethiol also contributes to the distinct scent signature associated with cancer, characterized by a combination of volatile organic compounds (VOCs). This intriguing scent profile is increasingly being explored for non-invasive early cancer diagnosis.

In a recent paper titled "Methanethiol: A Scent Mark of Dysregulated Sulfur Metabolism in Cancer,"  researchers unveiled new findings:

Tumor cells undergo metabolic adaptations to meet increased energy demands and enhance stress resilience. This includes dysregulation of sulfur metabolism and elevated levels of volatile sulfur compounds (VSCs) in cancer patients.

Methanethiol stands out as the predominant cancer-associated VSC and is being considered as a potential biomarker for non-invasive cancer diagnosis.

Within the gut microbiome of colorectal carcinoma (CRC) patients, gut bacteria, particularly methanethiol-producing strains like Fusobacterium nucleatum, are a significant source of exposure to methanethiol.

Selenium-binding protein 1 (SELENBP1) plays a crucial role in the rapid degradation of methanethiol through its methanethiol oxidase (MTO) activity.

Odor-based cancer screening methods, such as sniffer dogs and canine scent detection, even human feedback, have shown great promise in identifying lung and colorectal cancer patients, opening doors to non-invasive detection approaches.

The dysregulation of sulfur metabolism and the potential use of methanethiol as a biomarker, coupled with the innovative odor-based cancer screening methods, offer not just promising but transformative avenues for non-invasive cancer detection and cutting-edge research.

REFERENCE

Philipp TM, Scheller AS, Krafczyk N, Klotz LO, Steinbrenner H. Methanethiol: A Scent Mark of Dysregulated Sulfur Metabolism in Cancer. Antioxidants (Basel). 2023 Sep 19;12(9):1780. doi: 10.3390/antiox12091780. PMID: 37760083; PMCID: PMC10525899.

Olfactory Signatures and COVID-19

Olfactory disorders have a significant impact on human lives - be it a lost/distorted sense of smell or unpleasant odors affecting the sense of smell of others. 

Odortypes can be influenced by human leukocyte antigen (HLA) genes of the major histocompatibility complex (MHC), genes associated with stronger response to COVID-19 vaccine as well as the severity of this disease. HLA may also be related to people's perception of the odor of other people. 

Of course, these are not the only variables involved, and there are more potentially overlapping risk factors for olfaction, metabolic body odor (MEBO), including trimethylaminuria (TMAU), and COVID-19: FMO3, SELENBP1, HspA, UGT2A1/UGT2A2, etc. 

A new peer-reviewed paper reporting results of a decentralized observational study (NCT04832932) compared MEBO participants to general populations in respect to their response to COVID-19 vaccines and SARS-Co-V2 infections. 

Body odor flareups were observed in about 10% of malodor sufferers after vaccination, as preliminarily reported. This number was similar to flareups of other chronic symptoms in groups of participants with gastrointestinal and autoimmune disorders.  

Long-term worsening of body odor was observed by other researchers after COVID-19 vaccination in about ~1% of studied populations. Dry mouth leading to halitosis was 10 times more prevalent compared to flu vaccines. MEBO participants reported stronger reactions than general population pointing to genetic and microbiome influences beyond FMO3.  

A better understanding of systemic malodor conditions could offer leads for targeted therapies. Findings on genetic and microbiome overlaps between COVID-19 and MEBO could pave the way for precision medicine to address the unmet needs of odor sufferers.

REFERENCE

Gabashvili IS. The Incidence and Effect of Adverse Events Due to COVID-19 Vaccines on Breakthrough Infections: Decentralized Observational Study With Underrepresented Groups. JMIR Formative Research. 2022 Nov;6(11):e41914. DOI: 10.2196/41914. PMID: 36309347; PMCID: PMC9640199.

On Cabbage and Selenium Binding Protein 1

Mutations in the gene encoding Selenium Binding Protein (SELENBP1) on chromosome 1q21 were found in multiple individuals with extra-oral halitosis. These individuals had increased levels of methanethiol and dimethylsulfide in their breath perceived as unpleasantly cabbage-smelling. It was reported to worsen after drinking beer. 

The mutations responsible include rs1553204817 (OMIM: 604188.0001: c.1039G>T); rs758495626 (c.673G>T (p.Gly225Trp)), rs1357490520 (c.481+1G>A disrupting splice site), and rs1553204840 (c.985C>T)

SELENBP1 was identified as a methanethiol oxidase (MTO), catalyzing the conversion of methanethiol (H3C-SH) to hydrogen sulfide (H2S), hydrogen peroxide (H2O2) and formaldehyde (HCHO). If this enzyme is not properly functional, the body will be releasing more Methanethiol  - a volatile and toxic gas with the characteristic smell of rotten cabbage. We get this compound from food - not only the cancer-fighting cabbage family, including radishes, but also orange juice, pineapple, strawberries, asparagus, wheat bread, gruyere cheese, coffee, roasted filberts and even cooked rice. Water, cherries, apples, whole milk, spinach and citrusy fruits could counteract the odor in some individuals. 

Selenium binding protein1 (SELENBP1) has been also associated with a rare disease hypermethioninemia (sometimes accompanied by learning disabilities and neurological problems), several cancers and schizophrenia (downregulated at its onset and upregulated at later stages); hypertension and ischemic heart conditions. Dysregulation of SELENBP1 is common to Zika virus (ZIKV) and dengue infections, and Guillain-Barré syndrome. It was also found to COVID-19.

REFERENCES

Pol A, Renkema GH, Tangerman A, Winkel EG, Engelke UF, De Brouwer AP, Lloyd KC, Araiza RS, Van Den Heuvel L, Omran H, Olbrich H. Mutations in SELENBP1, encoding a novel human methanethiol oxidase, cause extraoral halitosis. Nature genetics. 2018 Jan;50(1):120-9.

Philipp TM, Will A, Richter H, Winterhalter PR, Pohnert G, Steinbrenner H, Klotz LO. A coupled enzyme assay for detection of selenium-binding protein 1 (SELENBP1) methanethiol oxidase (MTO) activity in mature enterocytes. Redox Biology. 2021 Jul 1;43:101972.

Lin X, Lin Z, Zhao X, Liu Z, Xu C, Yu B, Gao P, Wang Z, Ge J, Shen Y, Li L. Serum SELENBP1 and VCL Are Effective Biomarkers for Clinical and Forensic Diagnosis of Coronary Artery Spasm. International Journal of Molecular Sciences. 2022 Oct 31;23(21):13266.

Chau EJ, Mostaid MS, Cropley V, McGorry P, Pantelis C, Bousman CA, Everall IP. Downregulation of plasma SELENBP1 protein in patients with recent-onset schizophrenia. Progress in Neuro-Psychopharmacology and Biological Psychiatry. 2018 Jul 13;85:1-6.

Zhang X, Hong R, Bei L, Hu Z, Yang X, Song T, Chen L, Meng H, Niu G, Ke C. SELENBP1 inhibits progression of colorectal cancer by suppressing epithelial–mesenchymal transition. Open Medicine. 2022 Jan 1;17(1):1390-404.

Moni MA, Lio’ P. Genetic profiling and comorbidities of zika infection. The Journal of infectious diseases. 2017 Sep 15;216(6):703-12.

de Melo CV, Bhuiyan MA, Gatua WN, Kanyerezi S, Uzairue L, Abechi P, Kumar K, Rahmat J, Giwa A, Mwandira G, Olamilekan AM. Transcriptomic dysregulations associated with SARS-CoV-2 infection in human nasopharyngeal and peripheral blood mononuclear cells. bioRxiv. 2020 Jan 1.

Albert-Puleo M. Physiological effects of cabbage with reference to its potential as a dietary cancer-inhibitor and its use in ancient medicine. Journal of ethnopharmacology. 1983 Dec 1;9(2-3):261-72.