Enhanced ER-associated degradation of HMG CoA reductase causes embryonic lethality associated with Ubiad1 deficiency

Jo, Youngah; Kim, Steven S.; Garland, Kristina; Fuentes, Iris; DiCarlo, Lisa M.; Ellis, Jessie L; Fu, Xueyan; Booth, Sarah L.; Evers, B. Mark; DeBose‐Boyd, Russell A.

doi:10.7554/elife.54841

Cited by 15 publications

(13 citation statements)

References 47 publications

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“…While these studies may result in niche applications of statins, they do not explain the more widely reported dependency on GGPP, as ubiquinone and dolichol can be derived from FPP [60][61][62][63] (Figure 1). GGPP is utilized for the conversion of vitamin K1 to vitamin K2 [64] by UBIAD1, an enzyme that also directs HMGCR degradation [65,66]. GGPP-directed functions of UBIAD1 are not well studied in statin's anticancer effects.…”

Section: Challenges To Identifying Determinants Of Mevalonate Pathway Dependencymentioning

confidence: 99%

Targeting the Mevalonate Pathway in Cancer

Juarez

Fruman

2021

Trends in Cancer

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Section: Challenges To Identifying Determinants Of Mevalonate Pathway Dependencymentioning

confidence: 99%

Targeting the Mevalonate Pathway in Cancer

Juarez

Fruman

2021

Trends in Cancer

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“…Therefore, nonsterol mevalonate pathway products also control HMGCR levels, consistent with its key position upstream of the isoprenoid branch of the pathway. The importance of this accessory mode of regulation in whole-body metabolism is demonstrated by the embryonic lethality of UBIAD1 deficiency in mice, which can be rescued by the knock-in of degradation-resistant HMGCR (65).…”

Section: The Classic Control Enzyme -Hmgcrmentioning

confidence: 99%

Post-translational control of the long and winding road to cholesterol

Sharpe

Coates

Brown

2020

Journal of Biological Chemistry

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The synthesis of cholesterol requires more than 20 enzymes, many of which are intricately regulated. Post-translational control of these enzymes provides a rapid means for modifying flux through the pathway. So far, several enzymes have been shown to be rapidly degraded through the ubiquitin proteasome pathway in response to cholesterol and other sterol intermediates. Additionally, several enzymes have their activity altered through phosphorylation mechanisms. Most work has focused on the two rate-limiting enzymes: 3-hydroxy-3-methyl-glutaryl coenzyme A reductase and squalene monooxygenase. Here, we review current literature in the area to define some common themes in the regulation of the entire cholesterol synthesis pathway. We highlight the rich variety of inputs controlling each enzyme, discuss the interplay that exists between regulatory mechanisms, and summarize findings that reveal an intricately coordinated network of regulation along the cholesterol synthesis pathway. We provide a roadmap for future research into the post-translational control of cholesterol synthesis, and no doubt the road ahead will reveal further twists and turns for this fascinating pathway crucial for human health and disease.

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“…Unbound VK3 in circulation is highly reactive and easily excreted, not remaining in blood for a long period. The subsequent prenylation of VK3 to MK-4 at the enterocytes [ 11 ] or any other tissues (including testis; [ 13 ]) has been suggested, a reaction that seems to be catalyzed by the ubiquitously expressed UbiA prenyltransferase domain-containing protein 1 (Ubiad1) [ 8 , 14 ]. Nevertheless, orally administered MK-4 and MK-7 can be also converted to MK-4 [ 8 ] and thus, the previously described metabolic transformations of a certain amount of VK1 might be also applied to other members of the VK family [ 9 ].…”

Section: Vitamin K Metabolites Sources and Metabolismmentioning

confidence: 99%

Vitamin K in Vertebrates’ Reproduction: Further Puzzling Pieces of Evidence from Teleost Fish Species

2020

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Vitamin K (VK) is a fat-soluble vitamin that vertebrates have to acquire from the diet, since they are not able to de novo synthesize it. VK has been historically known to be required for the control of blood coagulation, and more recently, bone development and homeostasis. Our understanding of the VK metabolism and the VK-related molecular pathways has been also increased, and the two main VK-related pathways—the pregnane X receptor (PXR) transactivation and the co-factor role on the γ-glutamyl carboxylation of the VK dependent proteins—have been thoroughly investigated during the last decades. Although several studies evidenced how VK may have a broader VK biological function than previously thought, including the reproduction, little is known about the specific molecular pathways. In vertebrates, sex differentiation and gametogenesis are tightly regulated processes through a highly complex molecular, cellular and tissue crosstalk. Here, VK metabolism and related pathways, as well as how gametogenesis might be impacted by VK nutritional status, will be reviewed. Critical knowledge gaps and future perspectives on how the different VK-related pathways come into play on vertebrate’s reproduction will be identified and proposed. The present review will pave the research progress to warrant a successful reproductive status through VK nutritional interventions as well as towards the establishment of reliable biomarkers for determining proper nutritional VK status in vertebrates.

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Enhanced ER-associated degradation of HMG CoA reductase causes embryonic lethality associated with Ubiad1 deficiency

Cited by 15 publications

References 47 publications

Targeting the Mevalonate Pathway in Cancer

Targeting the Mevalonate Pathway in Cancer

Post-translational control of the long and winding road to cholesterol

Vitamin K in Vertebrates’ Reproduction: Further Puzzling Pieces of Evidence from Teleost Fish Species

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