6ESQ

Structure of the acetoacetyl-CoA thiolase/HMG-CoA synthase complex from Methanothermococcus thermolithotrophicus soaked with acetyl-CoA

Summary for 6ESQ

• Entry DOI: 10.2210/pdb6esq/pdb
• Descriptor: acetoacetyl-CoA thiolase, Pfam DUF35, HydroxyMethylGlutaryl-CoA synthase, ... (9 entities in total)
• Functional Keywords: isoprenoid synthesis, enzymatic channeling, mevalonate production, archaea, lipid biosynthesis, multi-enzymatic complex, scaffold protein, duf35 family, transferase
• Biological source: Methanothermococcus thermolithotrophicus; More
• Total number of polymer chains: 12
• Total formula weight: 381114.94

Authors

Voegeli, B.,Engilberge, S.,Girard, E.,Riobe, F.,Maury, O.,Erb, J.T.,Shima, S.,Wagner, T. (deposition date: 2017-10-24, release date: 2018-03-14, Last modification date: 2024-05-08)

Primary citation

Vogeli, B.,Engilberge, S.,Girard, E.,Riobe, F.,Maury, O.,Erb, T.J.,Shima, S.,Wagner, T.
Archaeal acetoacetyl-CoA thiolase/HMG-CoA synthase complex channels the intermediate via a fused CoA-binding site.
Proc. Natl. Acad. Sci. U.S.A., 115:3380-3385, 2018

PubMed Abstract: Many reactions within a cell are thermodynamically unfavorable. To efficiently run some of those endergonic reactions, nature evolved intermediate-channeling enzyme complexes, in which the products of the first endergonic reactions are immediately consumed by the second exergonic reactions. Based on this concept, we studied how archaea overcome the unfavorable first reaction of isoprenoid biosynthesis-the condensation of two molecules of acetyl-CoA to acetoacetyl-CoA catalyzed by acetoacetyl-CoA thiolases (thiolases). We natively isolated an enzyme complex comprising the thiolase and 3-hydroxy-3-methylglutaryl (HMG)-CoA synthase (HMGCS) from a fast-growing methanogenic archaeon, HMGCS catalyzes the second reaction in the mevalonate pathway-the exergonic condensation of acetoacetyl-CoA and acetyl-CoA to HMG-CoA. The 380-kDa crystal structure revealed that both enzymes are held together by a third protein (DUF35) with so-far-unknown function. The active-site clefts of thiolase and HMGCS form a fused CoA-binding site, which allows for efficient coupling of the endergonic thiolase reaction with the exergonic HMGCS reaction. The tripartite complex is found in almost all archaeal genomes and in some bacterial ones. In addition, the DUF35 proteins are also important for polyhydroxyalkanoate (PHA) biosynthesis, most probably by functioning as a scaffold protein that connects thiolase with 3-ketoacyl-CoA reductase. This natural and highly conserved enzyme complex offers great potential to improve isoprenoid and PHA biosynthesis in biotechnologically relevant organisms.

PubMed: 29531083
DOI: 10.1073/pnas.1718649115

Experimental method

X-RAY DIFFRACTION (2.95 Å)