The archaeal mevalonate pathway is a recently discovered modified version of the eukaryotic mevalonate pathway. This pathway is widely conserved in archaea, except for some archaeal lineages possessing the eukaryotic or other modified mevalonate pathways. Although the pathway seems almost exclusive to the domain Archaea, the whole set of homologous genes of the pathway is found in the metagenome-assembled genome sequence of an uncultivated bacterium, Candidatus Promineifilum breve, of the phylum Chloroflexota. To prove the existence of the archaea-specific pathway in the domain Bacteria, we confirmed the activities of the enzymes specific to the pathway, phosphomevalonate dehydratase and anhydromevalonate phosphate decarboxylase, because only these two enzymes are absent in closely related Chloroflexota bacteria that possess a different type of modified mevalonate pathway. The activity of anhydromevalonate phosphate decarboxylase was evaluated by carotenoid production via the archaeal mevalonate pathway reconstituted in Escherichia coli cells, whereas that of phosphomevalonate dehydratase was confirmed by an in vitro assay using the recombinant enzyme after purification and iron-sulfur cluster reconstruction. Phylogenetic analyses of some mevalonate pathway-related enzymes suggest an evolutionary route for the archaeal mevalonate pathway in Candidatus P. breve, which probably involves horizontal gene transfer events.IMPORTANCEThe recent discovery of various modified mevalonate pathways in microorganisms, such as archaea and Chloroflexota bacteria, has shed light on the complexity of the evolution of metabolic pathways, including those involved in primary metabolism. The fact that the archaeal mevalonate pathway, which is almost exclusive to the domain Archaea, exists in a Chloroflexota bacterium provides valuable insights into the molecular evolution of the mevalonate pathways and associated enzymes. Putative genes probably involved in the archaeal mevalonate pathway have also been found in the metagenome-assembled genomes of Chloroflexota bacteria. Such genes can contribute to metabolic engineering for the bioproduction of valuable isoprenoids because the archaeal mevalonate pathway is known to be an energy-saving metabolic pathway that consumes less ATP than other mevalonate pathways do.

The infectivity of Leishmania is determined by its ability to invade and evade host and its thriving capacity within the macrophage. Our study revealed the role of Leishmania donovani mevalonate kinase (MVK), an enzyme of mevalonate pathway in visceral leishmaniasis pathogenesis. Peritoneal exudate cells (PEC)-derived macrophages from BALB/c mice were infected with wild type (WT), MVK over expressing (MVK OE) and knockdown (KD) parasites and MVK OE parasites were found to be more infective than WT and MVK KD parasites. Incubation of macrophages with MVK OE parasites declined inducible nitric oxide synthase (iNOS) expression as well as nitric oxide (NO) production, both by 2 times in comparison to WT parasites. Moreover, ∼3 fold increase in Arginase1 expression indicated that MVK might induce polarization of macrophage towards M2, favouring the survival of parasite within the macrophages. Post 24 h infection of the macrophages with mutant strains, the levels of different cytokines (TNF-α, IL-12, IL-10 and IFN-γ) were measured. Infection of macrophages with MVK OE parasites showed an increase in the level of anti-inflammatory cytokine: IL-10 while infection with MVK KD parasites exhibited an increase in the level of pro-inflammatory cytokines: TNF-α, IL-12, and IFN-γ. Hence, Leishmania donovani mevalonate kinase (LdMVK) modulates macrophage functions and has a significant role in pathogenesis.

Hyperimmunoglobulin D syndrome (HIDS) is a rare but severe autoinflammatory disease with a poor prognosis if not diagnosed and treated early. Here, we report three cases of HIDS in children with typical clinical manifestations and a clear genetic diagnosis. Patient 1 experienced recurrent fever flares with a maculo-papular skin rash. Patient 2 presented with periodic fever, cholestasis, lymphadenopathy, aphthous stomatitis, arthralgia, and abdominal pain and underwent surgery for intestinal obstruction. Patient 3, a sibling of patient 2, presented with periodic fever and underwent a surgical procedure for intussusception. All three patients were administered interleukin (IL)-6 receptor antagonist (tocilizumab). The results showed that tocilizumab effectively reduced inflammatory flares. Early diagnosis and tocilizumab treatment are effective at improving the prognosis of HIDS patients.

Mevalonate kinase is a key regulator of the mevalonate pathway, subject to feedback inhibition by the downstream metabolite farnesyl pyrophosphate. In this study, we validated the hypothesis that monophosphonate compounds mimicking farnesyl pyrophosphate can inhibit mevalonate kinase. Exploring compounds originally synthesized as allosteric inhibitors of farnesyl pyrophosphate synthase, we discovered mevalonate kinase inhibitors with nanomolar activity. Kinetic characterization of the two most potent inhibitors demonstrated Ki values of 3.1 and 22 nm. Structural comparison suggested features of these inhibitors likely responsible for their potency. Our findings introduce the first class of nanomolar inhibitors of human mevalonate kinase, opening avenues for future research. These compounds might prove useful as molecular tools to study mevalonate pathway regulation and evaluate mevalonate kinase as a potential therapeutic target.

UNASSIGNED: This case highlights the potential for later-onset Hyper-IgD syndrome (HIDS) even beyond infancy. Clinicians evaluating children with recurrent fever, skin rash, and arthralgia should consider HIDS in the differential diagnosis, regardless of age. Early suspicion and genetic testing can lead to a timely diagnosis and targeted therapy with Anakinra, significantly improving patient outcomes.
UNASSIGNED: Hyper-IgD syndrome (HIDS) is a rare autosomal recessive autoinflammatory disorder characterized by recurrent episodes of fever, lymphadenopathy, arthralgia, diarrhea, abdominal pain, and skin rash. In this case report, we present a 5-year-old girl from Tajikistan with a mutation in the mevalonate kinase (MVK) gene, which is consistent with a diagnosis of HIDS. The clinical symptoms of the patient are described, along with immunological, hematological, and biochemical findings collected from the evaluation in the rheumatology clinic. Additionally, whole-exome sequencing revealed a heterozygous missense variation in exon 4 of the MVK gene. The diagnosis of HIDS in this case occurred at a later age than typically observed, emphasizing the importance of considering this condition even in older patients. This report highlights the broad clinical phenotype of MVK and the need for increased awareness among healthcare professionals regarding its clinical presentation and management.

BACKGROUND: Research has shown that epigenetic modification are involved the regulation of diapause in bivoltine silkworms (Bombyx mori), but it remains unclear how epigenetic modification in response to environmental signals precisely to regulate the diapause processing of bivoltine B. mori.
RESULTS: In this study, the diapause terminated eggs of bivoltine B. mori, Qiufeng (QF) were divided into two groups: a QFHT group incubated at 25 °C with a natural day/night cycle to produce diapause eggs, and a QFLT group incubated at 16.5 °C in darkness to produce non-diapause eggs. On the 3rd day of the pupal stage, the total RNAs of the eggs were extracted and their N6-adenosine methylation (m6A) abundances were analyzed to explore the effects of m6A methylation on diapause in the silkworm. The results showed that 1984 m6A peaks are shared, 1563 in QFLT and 659 in QFHT. The m6A methylation level of the QFLT group was higher than that of the QFHT one in various signaling pathways. The m6A methylation rate of mevalonate kinase (MK) in the insect hormone synthesis pathway was significantly different between the two groups. The knockdown of MK by RNA interference in the pupae of QFLT resulted in females laying diapause eggs rather than non-diapause eggs after mating.
CONCLUSIONS: m6A methylation involves in the diapause regulation of bivoltine B. mori by changing the expression levels of MK. This result provides a clearer image of the environmental signals on the regulation of diapause in bivoltine silkworms.

The production of terpenoids from engineered microbes contributes markedly to the bioeconomy by providing essential medicines, sustainable materials, and renewable fuels. The mevalonate pathway leading to the synthesis of terpenoid precursors has been extensively targeted for engineering. Nevertheless, the importance of individual pathway enzymes to the overall pathway flux and final terpenoid yield is less known, especially enzymes that are thought to be non-rate-limiting. To investigate the individual contribution of the five non-rate-limiting enzymes in the mevalonate pathway, we created a combinatorial library of 243 Saccharomyces cerevisiae strains, each having an extra copy of the mevalonate pathway integrated into the genome and expressing the non-rate-limiting enzymes from a unique combination of promoters. High-throughput screening combined with machine learning algorithms revealed that the mevalonate kinase, Erg12p, stands out as the critical enzyme that influences product titer. ERG12 is ideally expressed from a medium-strength promoter which is the \'sweet spot\' resulting in high product yield. Additionally, a platform strain was created by targeting the mevalonate pathway to both the cytosol and peroxisomes. The dual localization synergistically increased terpenoid production and implied that some mevalonate pathway intermediates, such as mevalonate, isopentyl pyrophosphate (IPP), and dimethylallyl pyrophosphate (DMAPP), are diffusible across peroxisome membranes. The platform strain resulted in 94-fold, 60-fold, and 35-fold improved titer of monoterpene geraniol, sesquiterpene α-humulene, and triterpene squalene, respectively. The terpenoid platform strain will serve as a chassis for producing any terpenoids and terpene derivatives.

OBJECTIVE: Mevalonate kinase deficiency (MKD) is an autosomal recessive autoinflammatory disease characterized by recurrent systemic inflammation attacks. Despite interconnections with inflammation, thrombosis is rare or underreported in MKD. Our goal is to report evidence of uncontrolled inflammation as the cause of ischemic stroke.
METHODS: Case report.
RESULTS: A 39-year-old French-Canadian patient consulted for stroke. He reported a previous diagnosis of familial Mediterranean fever and hospitalizations nearly monthly since birth for recurrent inflammatory attacks despite colchicine prophylaxis. Attacks were triggered by infections or stress, lasted 3-7 days, and included fever up to 41°C, painful lymphadenopathies, abdominal pain, polyarthralgia and maculopapular rash. Stroke culminated his most recent inflammatory attack. Brain MRI confirmed an acute infarct, without chronic ischemic damage. Blood tests documented increased C-reactive protein, amyloid A and immunoglobulin-D. Prothrombotic and autoantibody tests, cervicocephalic CT-angiography, echocardiography, cardiac monitoring, and toxic screen were unremarkable. Infections were excluded. His only sister had similar attacks. In both cases, sequencing of 32 autoinflammatory-associated genes identified two pathogenic mevalonate kinase mutations. Their non-consanguineous parents, half-brother and four children were asymptomatic. Following treatment with anti-interleukin-1beta monoclonal antibodies, he no longer had inflammatory attacks or stroke in >4 years.
CONCLUSIONS: This MKD patient experienced an ischemic stroke during an attack, attributed to uncontrolled inflammation. Investigations excluded other stroke etiologies. Recurrent febrile attacks starting before age 1 and lasting >3 days, gastrointestinal symptoms, painful lymphadenopathies, maculopapular rash, triggers, aphthous stomatitis, non-Mediterranean ancestry, and ineffectiveness of colchicine prophylaxis are consistent with MKD. Anti-interleukin-1 therapy prevents recurrent autoinflammatory attacks.

Porokeratosis is a keratinization disorder with unclear etiopathogenesis, varied clinical presentation and characteristic histopathology, and is usually unresponsive to current therapeutic options. Until now, it was considered to be a clonal disorder with immunity, ultra violet radiation and other factors playing important roles in etiopathogenesis. It is now known that abnormalities in the mevalonate pathway are responsible for this clonal keratinization abnormality. New variants of porokeratosis like eruptive bullous, pruriginous, lichen planus like, follicular variants and porokeratoma have been described. While the cornoid lamella is the classical histopathologic feature, dermoscopy and reflectance confocal microscopy make the diagnosis clearer. Development of malignancy in a few variants is a concern. Linear, disseminated superficial actinic and giant lesions are most prone to developing malignancies. Bowen\'s disease, squamous cell carcinoma, basal cell carcinoma and even melanoma have been reported in cases of long-standing porokeratosis. Newer modalities of therapy such as photodynamic therapy, ingenol mebutate and HMGCoA inhibitors may play a role in the future.

Leishmaniasis comprises of a wide variety of diseases, caused by protozoan parasite belonging to the genus Leishmania. Leishmania parasites undergo different types of stress during their lifetime and have developed strategies to overcome this damage. Identifying the mechanistic approach used by the parasite in dealing with the stress is of immense importance for unfolding the survival strategy adopted by the parasite. Mevalonate kinase (MVK) is an important regulatory factor in the mevalonate pathway in both bacteria and eukaryotes. In this study, we explored the role of Leishmania donovani mevalonate kinase (LdMVK) in parasite survival under stress condition. Hydrogen peroxide (H2O2) and menadione, the two known oxidants were used to carry out the experiments. The MVK expression was found to be up regulated ∼2.1 fold and ∼2.3 fold under oxidative stress condition and under the effect of anti-Leishmania drug, AmBisome respectively. The cell viability declined under the effect of MVK inhibitor viz: vanadyl sulfate (VS). The level of intracellular ROS was also found to be increased under the effect of MVK inhibitor. To confirm the findings, LdMVK over expression (LdMVK OE) and LdMVK knockdown (LdMVK KD) parasites were generated. The level of ergosterol, an important component of plasma membrane in L. donovani, was observed and found to be reduced by nearly 60 % in LdMVK KD parasite and increased by nearly 30 % in LdMVK OE parasites as compared to wild type. However, the ergosterol content was found to be elevated under oxidative stress. Furthermore, LdMVK was also found to be associated with maintaining the plasma membrane integrity and also in preventing the peroxidation of cellular lipids when exposed to oxidative stress. The above data clearly suggests that MVK has a vital role in protecting the parasite from oxidative stress. These findings may also explore the contribution of LdMVK in drug unresponsiveness which may help in future rational drug designing for leishmaniasis.