Evolutionary Origins of the Multienzyme Architecture of Giant Fungal Fatty Acid Synthase

Abstract

Fungal fatty acid synthase (fFAS) is a key paradigm for the evolution of complex multienzymes. Its 48 functional domains are embedded in a matrix of scaffolding elements, which comprises almost 50% of the total sequence and determines the emergent multienzymes properties of fFAS. Catalytic domains of fFAS are derived from monofunctional bacterial enzymes, but the evolutionary origin of the scaffolding elements remains enigmatic. Here, we identify two bacterial protein families of noncanonical fatty acid biosynthesis starter enzymes and trans-acting polyketide enoyl reductases (ERs) as potential ancestors of scaffolding regions in fFAS. The architectures of both protein families are revealed by representative crystal structures of the starter enzyme FabY and DfnA-ER. In both families, a striking structural conservation of insertions to scaffolding elements in fFAS is observed, despite marginal sequence identity. The combined phylogenetic and structural data provide insights into the evolutionary origins of the complex multienzyme architecture of fFAS.

Fatty Acid Biosynthesis: Chain‐Length Regulation and Control

“…At a later evolutionary stage, splitting into two genes at various sites occurred. This led to a fungal FAS family divided in gene topological variants …”

“…Alternative scenarios hypothesize that multifunctional FASs first emerged in eukaryotes as products of intronic recombination and at a later stage spread into prokaryotes through horizontal gene transfer. Although this alternative evolutionary route cannot be entirely discounted, the gene fusion hypothesis is today the dominant doctrine …”

Evolution of Enzyme Kinetic Mechanisms

“…One such enzyme is fungal fatty acid synthase, which has played a key role in the evolution of complex multi-enzymes. It has 48 functional domains, which are embedded in a matrix of scaffolding elements (Bukhari et al 2014). Mechanism pathways for multi-substrate multi-product enzyme-catalysed reactions can become very complex and lead to kinetic models comprising several terms (Bornadel et al 2013) or quite simple terms, such as random, sequential binding mechanisms (Burke et al 2013).…”

Stereocontrol within polyketide assembly lines

“…The medium chain dehydrogenase/reductase (MDR) ERs from cis -AT PKSs are discussed here since much less is known about the TIM-barrel ERs of trans -AT PKSs, although a structure of a trans -ER from the difficidin PKS provides a basis for understanding its embedded relatives (DifA-ER; 2.30 Å-resolution; PDB: 4CW5). 46 …”