H E A L T H I N N O V A T I O N , O V E R C O M I N G D I S E A S E S A N D P A N D E M I C S

S C I E N T I F I C H I G H L I G H T S

3 2 H I G H L I G H T S 2 0 2 3 I

X-ray crystallography reveals a new link between metabolism and epigenetics Crystallographic data have revealed how a metabolic enzyme best known for balancing nucleotides can also play a key role in the epigenetic regulation of fatty acid synthesis a process important in type 2 diabetes and other diseases.

De novo lipogenesis (DNL) is the metabolic pathway used primarily by the liver and adipose (fat-storing) tissue to synthesise fatty acids from excess carbohydrates or other precursors [1]. An increased rate of DNL is observed in cancer and in many characteristically Western diseases of affluence, such as metabolic disorder, type 2 diabetes, chronic liver disease and cardiovascular disease [2]. In response to metabolic changes, the liver and adipose tissue regulate the expression of genes encoding proteins important for de novo lipogenesis (DNL) through a variety of mechanisms. One of these processes involves the introduction of acetyl groups into histones, the proteins that package DNA, without altering their DNA sequence, thereby affecting gene expression. However, the molecular details that underlie this level of regulation are poorly understood.

In this work, an unexpected breakthrough has come from an initially unrelated investigation into the hyper- acetylation of chromatin during mammalian sperm development. Among the most highly abundant factors in male germ cells that bind acetyl-coenzyme A (acetyl- CoA), a key metabolite for histone acetylation, the protein NME1 and its closely related variant NME2 were identified. These ubiquitous metabolic enzymes, collectively called NME1/2, are best known for balancing proportions of nucleotides in the cell. They perform this role by transferring a phosphate group from a nucleoside triphosphate, typically ATP, to a nucleoside diphosphate. The surprising discovery of NME1/2 as a factor that

Fig. 19: Ligand recognition by NME1. a) Crystal structure of NME1, a hexameric enzyme with D3 symmetry. b) Details of the recognition of the nucleotide moiety of acetyl-CoA (AcCoA). Direct and water-mediated hydrogen bonds

between NME1 and acetyl-CoA are shown as red and grey dashed lines, respectively. c) Superimposition of the acetyl-CoA and ADP ligands showing the distinct binding mode of acetyl-CoA, achieved through a rotation of the adenine base and a

repositioning of the α- and β-phosphate groups.