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UCL iGEM 2016 | BioSynthAge


See how we are re-designing the microbiome to lower blood pressure
as way of reducing the chance of age-related complications with the cardiovascular system.


The problem: hypertension

High blood pressure (HBP) or hypertension constitutes a major cause of cardiovascular disease and mortality throughout the world, estimated to affect more than 65% of people over 65 years of age (1). Underlying HBP is the increase in peripheral resistance associated with the progressive decrease in the bioavailability of nitric oxide (NO) observed in aging (2). NO plays an important role in regulating blood pressure as it mediates vascular dilatation and therefore represents a therapeutic target.

Our approach: an L-arginine-overproducing device

Our team designed Biobricks which could be used to create an L-arginine overproducing strain which could potentially be applied as a probiotic counteracting hypertension.

L-Arginine (2-amino-5-guanidinovaleric acid) is a conditionally essential amino acid, particularly important in people with hypertension and type II diabetes as these conditions are accompanied by an increase in the activity of the enzyme that degrades L-arginine (known as arginase), resulting in L-arginine deficiency. This amino acid is very versatile because it acts as a precursor of numerous molecules including NO, urea, agmatine, glutamate, proline and creatine (3). One interesting property of L-arginine is its potential to increase protein solubility and suppress protein aggregation (due to the change in the surface tension of proteins caused by interaction with proteins or the water surrounding them) - it has been shown to destabilize and remove mature oral biofilms preventing plaque, elevate dental plaque pH preventing tooth demineralization as well as the growth of aciduric bacteria and diminish infectivity of envelope viruses, e.g. herpes simplex and influenza. It has been indicated that L-arginine intake in doses larger than standard dietary consumption can improve symptoms of cardiovascular disease (4) and insulin sensitivity (5), aid in the healing of wounds (6) and gastric ulcers (7) and relieve stress (8).

The amino acid is synthesized in the so-called linear pathway (Fig. 1) from L-glutamate. The initial enzyme in the pathway, N-acetylglutamate synthase (NAGS), is inhibited by L-arginine in a negative feedback loop (9). Another source of inhibition of the pathway is ArgR, the common repressor of L-arginine biosynthetic genes for which the amino acid acts as a co-repressor (10).

Our team designed Biobricks: BBa_K1954006, BBa_K1954008 and BBa_K1954009, to overcome the limitations of the linear pathway. The mutagenized version of NAGS is resistant to inhibition by L-arginine. The ARG box is a binding sequence for ArgR and could be introduced into a high-copy number plasmid to titrate the repressor away from the regulatory sequences of biosynthetic genes. In addition, our team made a Biobrick for the exporter of L-arginine under a constitutive promoter to maximize the transport of the amino acid out of the cell.


Fig. 1. Ways to target the linear L-arginine biosynthetic pathway for increased synthesis of the amino acid.



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