Synthetic Isoprenoid Pathways for Carbon and ATP Efficiency

Resolve Bottlenecks,
Find Innovative SolutionsGenerate Solutions

Solution Overview

Problem

The existing native pathways for isoprenoid synthesis, such as the mevalonate (MVA) and 2-C-methyl-D-erythritol 4-phosphate/1-deoxy-D-xylulose 5-phosphate (DXP) pathways, are inefficient in terms of carbon and energy usage, leading to significant losses and high ATP consumption.

Innovation Solution

Employing enzyme combinations and recombinant microbes to create novel synthetic metabolic pathways that utilize Claisen, aldol, or acyloin condensation reactions to produce isoprenoid precursors and derivatives, including prenylated aromatic compounds, with improved carbon and energy efficiency.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Loss of energy

If native pathways (MVA or DXP) are used for isoprenoid synthesis, then isoprenoid products can be produced, but carbon and energy efficiency is poor with significant carbon loss and high ATP consumption

Engineering Contradiction:

ImproveATP consumptionVSAvoidisoprenoid production efficiency

Core Design Contradiction:

Loss of energyVSProductivity

Solution Approach 1:

The patent changes the biochemical parameters of the synthesis pathway by replacing the native MVA or DXP pathways with an alternative pathway using thiolase-catalyzed condensation of acetyl-CoA and propionyl-CoA. This parameter change results in reduced ATP consumption (from 3 ATP equivalents per C5 unit to approximately 1 ATP equivalent) and improved carbon efficiency (from 67% carbon loss to approximately 33% carbon loss), thereby resolving the contradiction between energy efficiency and productivity.

Inventive Principle:

Principle #35Parameter changes

2Loss of substance

If native pathways (MVA or DXP) are used for isoprenoid synthesis, then isoprenoid products can be produced, but carbon loss is significant

Engineering Contradiction:

Improvecarbon lossVSAvoidisoprenoid production efficiency

Core Design Contradiction:

Loss of substanceVSProductivity

Solution Approach 1:

Inventive Principle:

Principle #35Parameter changes

3Productivity

If alternative synthetic pathways are used to improve carbon and energy efficiency, then production efficiency increases, but pathway complexity increases

Engineering Contradiction:

Improveisoprenoid production efficiencyVSAvoidmetabolic pathway complexity

Core Design Contradiction:

ProductivityVSDevice complexity

Solution Approach 1:

The patent divides the complex biosynthesis process into modular enzymatic steps: thiolase-catalyzed condensation to form acetoacetyl-CoA, followed by reduction to D-beta-hydroxybutyryl-CoA, and subsequent conversion to isoprenoid precursors. This segmentation allows each step to be independently optimized and controlled, managing pathway complexity while maintaining high productivity and efficiency.

Inventive Principle:

Principle #1Segmentation

Applied Scientific Principles

This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.

Function Achieved in This Case

These pathways enhance the production of isoprenoids and derivatives by reducing carbon and energy losses, enabling the synthesis of a diverse range of products with increased efficiency.

Implementation Method 1

thiolase-catalyzed condensation of acetyl-CoA and propionyl-CoA

Methodology Applied

Scientific EffectCondensation reaction: Chemical Bonding

Implementation Method 2

thiolase-catalyzed condensation

Methodology Applied

Scientific EffectEnzyme catalysis: Enzyme

Implementation Method 3

reduction to D-beta-hydroxybutyryl-CoA

Methodology Applied

Scientific EffectReduction reaction: Reduction

Implementation Method 4

converted into isopentenyl pyrophosphate and dimethylallyl pyrophosphate

Methodology Applied

Scientific EffectMetabolic pathway conversion: Chemical Bonding

Data Source

PatentUS12460234B2Synthesis of isoprenoids and derivatives

Publication Date: 2025.11.04 WILLIAM MARCH RICE UNIVERSITY

AI summary

This disclosure generally relates to the use of enzyme combinations or recombinant microbes comprising same to make isoprenoid precursors, isoprenoids and derivatives thereof including prenylated aromatic compounds. Novel metabolic pathways exploiting Claisen, aldol, and acyloin condensations are used instead of the natural mevalonate (MVA) pathway or 1-deoxy-d-xylulose 5-phosphate (DXP) pathways for generating isoprenoid precursors such as isopentenyl pyrophosphate (IPP), dimethylallyl pyrophosphate (DMAPP), and geranyl pyrophosphate (GPP). These pathways have the potential for better carbon and or energy efficiency than native pathways. Both decarboxylative and non-carboxylative condensations are utilized, enabling product synthesis from a number of different starting compounds. These condensation reactions serve as a platform for the synthesis of isoprenoid precursors when utilized in combination with a variety of metabolic pathways and enzymes for carbon rearrangement and the addition/removal of functional groups. Isoprenoid alcohols are key intermediary products for the production of isoprenoid precursors in these novel synthetic metabolic pathways. These precursors can be modified to various isoprenoid products through prenyl transferase, terpene synthase, or terpene cyclases. The production of prenylated aromatic compounds is achieved through prenyl transfer of the hydrocarbon units of isoprenoid precursors to polyketides.