7uli

Apo HMG-CoA Reductase from Arabidopsis thaliana (HMG1)Apo HMG-CoA Reductase from Arabidopsis thaliana (HMG1)

Structural highlights

7uli is a 1 chain structure with sequence from Arabidopsis thaliana. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.9Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

HMDH1_ARATH Catalyzes the synthesis of mevalonate, the specific precursor of all isoprenoid compounds present in plants.^[1] ^[2] ^[3] ^[4]

Publication Abstract from PubMed

Decades of intense herbicide use has led to resistance in weeds. Without innovative weed management practices and new herbicidal modes of action, the unabated rise of herbicide resistance will undoubtedly place further stress upon food security. HMGR (3-hydroxy-3-methylglutaryl-coenzyme A reductase) is the rate limiting enzyme of the eukaryotic mevalonate pathway successfully targeted by statins to treat hypercholesterolemia in humans. As HMGR inhibitors have been shown to be herbicidal, HMGR could represent a mode of action target for the development of herbicides. Here, we present the crystal structure of a HMGR from Arabidopsis thaliana (AtHMG1) which exhibits a wider active site than previously determined structures from different species. This plant conserved feature enables the rational design of specific HMGR inhibitors and we develop a tolerance trait through sequence analysis of fungal gene clusters. These results suggest HMGR to be a viable herbicide target modifiable to provide a tolerance trait.

A fungal tolerance trait and selective inhibitors proffer HMG-CoA reductase as a herbicide mode-of-action.,Haywood J, Breese KJ, Zhang J, Waters MT, Bond CS, Stubbs KA, Mylne JS Nat Commun. 2022 Sep 22;13(1):5563. doi: 10.1038/s41467-022-33185-0. PMID:36137996^[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Suzuki M, Kamide Y, Nagata N, Seki H, Ohyama K, Kato H, Masuda K, Sato S, Kato T, Tabata S, Yoshida S, Muranaka T. Loss of function of 3-hydroxy-3-methylglutaryl coenzyme A reductase 1 (HMG1) in Arabidopsis leads to dwarfing, early senescence and male sterility, and reduced sterol levels. Plant J. 2004 Mar;37(5):750-61. doi: 10.1111/j.1365-313x.2004.02003.x. PMID:14871314 doi:http://dx.doi.org/10.1111/j.1365-313x.2004.02003.x
↑ Ohyama K, Suzuki M, Masuda K, Yoshida S, Muranaka T. Chemical phenotypes of the hmg1 and hmg2 mutants of Arabidopsis demonstrate the in-planta role of HMG-CoA reductase in triterpene biosynthesis. Chem Pharm Bull (Tokyo). 2007 Oct;55(10):1518-21. doi: 10.1248/cpb.55.1518. PMID:17917299 doi:http://dx.doi.org/10.1248/cpb.55.1518
↑ Nieto B, Fores O, Arro M, Ferrer A. Arabidopsis 3-hydroxy-3-methylglutaryl-CoA reductase is regulated at the post-translational level in response to alterations of the sphingolipid and the sterol biosynthetic pathways. Phytochemistry. 2009 Jan;70(1):53-9. doi: 10.1016/j.phytochem.2008.10.010. Epub, 2008 Nov 27. PMID:19041104 doi:http://dx.doi.org/10.1016/j.phytochem.2008.10.010
↑ Suzuki M, Nakagawa S, Kamide Y, Kobayashi K, Ohyama K, Hashinokuchi H, Kiuchi R, Saito K, Muranaka T, Nagata N. Complete blockage of the mevalonate pathway results in male gametophyte lethality. J Exp Bot. 2009;60(7):2055-64. doi: 10.1093/jxb/erp073. Epub 2009 Apr 10. PMID:19363204 doi:http://dx.doi.org/10.1093/jxb/erp073
↑ Haywood J, Breese KJ, Zhang J, Waters MT, Bond CS, Stubbs KA, Mylne JS. A fungal tolerance trait and selective inhibitors proffer HMG-CoA reductase as a herbicide mode-of-action. Nat Commun. 2022 Sep 22;13(1):5563. doi: 10.1038/s41467-022-33185-0. PMID:36137996 doi:http://dx.doi.org/10.1038/s41467-022-33185-0

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OCA

[1] Suzuki M, Kamide Y, Nagata N, Seki H, Ohyama K, Kato H, Masuda K, Sato S, Kato T, Tabata S, Yoshida S, Muranaka T. Loss of function of 3-hydroxy-3-methylglutaryl coenzyme A reductase 1 (HMG1) in Arabidopsis leads to dwarfing, early senescence and male sterility, and reduced sterol levels. Plant J. 2004 Mar;37(5):750-61. doi: 10.1111/j.1365-313x.2004.02003.x. PMID:14871314 doi:http://dx.doi.org/10.1111/j.1365-313x.2004.02003.x

[2] Ohyama K, Suzuki M, Masuda K, Yoshida S, Muranaka T. Chemical phenotypes of the hmg1 and hmg2 mutants of Arabidopsis demonstrate the in-planta role of HMG-CoA reductase in triterpene biosynthesis. Chem Pharm Bull (Tokyo). 2007 Oct;55(10):1518-21. doi: 10.1248/cpb.55.1518. PMID:17917299 doi:http://dx.doi.org/10.1248/cpb.55.1518

[3] Nieto B, Fores O, Arro M, Ferrer A. Arabidopsis 3-hydroxy-3-methylglutaryl-CoA reductase is regulated at the post-translational level in response to alterations of the sphingolipid and the sterol biosynthetic pathways. Phytochemistry. 2009 Jan;70(1):53-9. doi: 10.1016/j.phytochem.2008.10.010. Epub, 2008 Nov 27. PMID:19041104 doi:http://dx.doi.org/10.1016/j.phytochem.2008.10.010

[4] Suzuki M, Nakagawa S, Kamide Y, Kobayashi K, Ohyama K, Hashinokuchi H, Kiuchi R, Saito K, Muranaka T, Nagata N. Complete blockage of the mevalonate pathway results in male gametophyte lethality. J Exp Bot. 2009;60(7):2055-64. doi: 10.1093/jxb/erp073. Epub 2009 Apr 10. PMID:19363204 doi:http://dx.doi.org/10.1093/jxb/erp073

[5] Haywood J, Breese KJ, Zhang J, Waters MT, Bond CS, Stubbs KA, Mylne JS. A fungal tolerance trait and selective inhibitors proffer HMG-CoA reductase as a herbicide mode-of-action. Nat Commun. 2022 Sep 22;13(1):5563. doi: 10.1038/s41467-022-33185-0. PMID:36137996 doi:http://dx.doi.org/10.1038/s41467-022-33185-0

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