Name: Aamna Butt

Date of submission: 1st May 2023

Instructor: Prof. Habib Nasir

Course: CH-475
Spring 2023

Biosynthesis of Quinine

1. Summary:

Quinine is a natural product with significant medical applications, particularly in the treatment of

malaria. However, the low abundance of quinine in nature has limited its availability. Therefore,

alternative methods of quinine production are needed. Recent advances in biotechnology and

synthetic biology have provided opportunities to improve the production of quinine through

metabolic engineering and synthetic biology approaches. I have briefly discussed the current state of

research on the biosynthesis of quinine, highlighting the progress that has been made and the

challenges that remain.

2. Introduction and history:

Quinine is a naturally occurring alkaloid that has been used

as an antimalarial drug for centuries. The bark of the

cinchona tree, from which quinine is extracted, was used by

indigenous peoples in South America for the treatment of

fevers and malaria. The medicinal properties of cinchona

bark were first introduced to Europe in the 17th century, and

by the 19th century, quinine had become the primary

treatment for malaria. However, the production of quinine

was limited by the availability of cinchona bark and the

difficulty of extracting and purifying the alkaloid. [1]

pathway was elucidated in the 1970s. The pathway involves the condensation of two molecules of

anthranilic acid to form a dihydroquinoline intermediate, which is then converted to a quinoline

intermediate. This quinoline intermediate is then hydroxylated at the 3-position and oxidized to form

quinine. [2]

The biosynthesis of quinine has been the subject of extensive research in recent years, with a focus

on improving the efficiency and yield of quinine production. Metabolic engineering and synthetic

biology approaches have been used to design and construct new biosynthetic pathways for quinine

production, with the ultimate goal of developing a more sustainable and cost-effective method of

producing this important drug. These approaches involve using computational tools to design new

enzymes and pathways that are optimized for quinine production, as well as using genetic

engineering techniques to introduce these pathways into host organisms. [3]

In addition to its use as an antimalarial drug, quinine has also been used in the production of tonic

water and other beverages. The bitter taste of quinine makes it a popular ingredient in tonic water,

which was originally developed as a way to make the bitter taste of quinine more palatable. Today,

tonic water is a popular mixer for cocktails and is enjoyed by people all over the world. [4].

3. Synthesis of quinine:

Recent advances in biotechnology and synthetic biology have opened up new opportunities for the

biosynthesis of quinine. Metabolic engineering approaches involve modifying the metabolic

pathways of microorganisms to produce quinine through synthetic biosynthetic pathways. One

promising approach is to use the genes involved in the biosynthesis of related alkaloids, such as

artemisinin, to produce quinine. This has been achieved in yeast and bacteria, resulting in the

production of small quantities of quinine. [5]

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Synthetic biology approaches involve designing new enzymes and biosynthetic pathways that are

optimized for quinine production. This involves using computational tools to design new enzymes

and pathways that can be expressed in microorganisms to produce quinine. Synthetic biology has the

potential to increase the yield and efficiency of quinine production by enabling the production of

enzymes that are not found in nature. [6].

While significant progress has been made in the biosynthesis of quinine using metabolic engineering

and synthetic biology, there are still challenges that need to be addressed. One of the major

challenges is the low yield of quinine production. To make the biosynthesis of quinine commercially

viable, it is necessary to improve the yield of quinine production to match the demand for this

important drug. Another challenge is the high cost of production. Currently, the production of

quinine using biotechnology and synthetic biology is more expensive than traditional extraction

methods, and reducing the cost of production will be crucial for the widespread adoption of this

approach. [7]

3.1. Total Synthesis of quinine by Woodward:

3.1.1. Synthesis of starting material: (Reference: [15], [16], [17])

Reference: [15], [16], [17]

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3.2.

Stereo-selective synthesis of quinine by Milan Uskokovic: [8]

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3.3. The key challenges to quinine production:

Improving the efficiency and

yield of quinine production

using biotechnology and

synthetic biology approaches is

a major challenge that needs to

be addressed. One of the key

challenges is the lack of

understanding of the biosynthetic pathway for quinine. While some of the genes and enzymes

involved in quinine biosynthesis have been identified, the complete biosynthetic pathway is not yet

fully understood. This makes it difficult to engineer microorganisms to produce quinine efficiently.

More research is needed to fully understand the biosynthesis of quinine, which will enable the design

of more effective metabolic engineering and synthetic biology approaches. [9]

Another challenge is the toxicity of quinine. Quinine is a toxic compound, and high concentrations of

quinine can be harmful to human health. This toxicity limits the amount of quinine that can be

produced by microorganisms, and makes it difficult to scale up production to meet commercial

demand. To address this challenge, researchers are exploring ways to engineer microorganisms to

produce fewer toxic derivatives of quinine. This will enable the production of larger quantities of

quinine that are safe for human consumption. [10].

Finally, the scale-up of production is a major challenge that needs to be addressed. While the

biosynthesis of quinine using biotechnology and synthetic biology approaches has shown that the

production of quinine using these approaches is still in the research phase. Scaling up production to

meet commercial demand will require significant investment and infrastructure, and there are

regulatory issues that need to be addressed. Ensuring that the biosynthesis of quinine is safe,

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environmentally friendly, and economically viable will be crucial for the widespread adoption of this

approach. [9].

3.4. Prospects for the commercial production of quinine and regularity issues:

The prospects for the commercial

production of quinine using

biotechnology and synthetic biology

approaches are promising, but there

are still challenges that need to be

addressed. One of the key

advantages of using biotechnology

and synthetic biology to produce

quinine is the potential to reduce the environmental impact of quinine production. Traditional

extraction methods for quinine involve the use of large quantities of solvents, which can be harmful

to the environment. In contrast, the biosynthesis of quinine using microorganisms is more

environmentally friendly, as it produces less waste and requires fewer resources. [11].

Another advantage of using biotechnology and synthetic biology to produce quinine is the potential

to reduce the cost of production. While the cost of production is currently higher than traditional

extraction methods, the cost is likely to decrease as the technology advances and production methods

are optimized. This could make quinine more affordable and accessible to people in developing

countries, where malaria is endemic. [11].

However, there are regulatory issues that need to be addressed before the commercial production of

quinine using biotechnology and synthetic biology approaches can be realized. One of the key issues

is the safety and efficacy of biosynthetic quinine. Regulatory agencies will need to ensure that

biosynthetic quinine is safe and effective for human consumption, and that it meets the same quality

standards as traditionally extracted quinine. [12].

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Another regulatory issue is intellectual property rights. As the technology for the biosynthesis of

quinine advances, there may be issues surrounding patents and intellectual property. This could limit

the availability and affordability of biosynthetic quinine, particularly in developing countries where

access to essential medicines is often limited. [12]

4. Conclusion:

In conclusion, the biosynthesis of quinine using metabolic engineering and synthetic biology

approaches has been the focus of extensive research in recent years. Significant progress has been

made in identifying the genes and pathways involved in quinine biosynthesis, and in developing new

biosynthetic pathways using synthetic biology techniques. However, there are still significant

challenges that need to be addressed in order to improve the efficiency and yield of production, such

as optimizing the expression and activity of biosynthetic enzymes, improving the availability of

precursor molecules, and balancing metabolic pathways to maximize the production of quinine.

Furthermore, the prospects for the commercial production of quinine using biotechnology and

synthetic biology approaches are promising. This approach offers exciting possibilities for improving

the production of quinine and making it more accessible to people in developing countries where

malaria is endemic. However, it is crucial to address regulatory issues such as the safety and efficacy

of biosynthetic quinine and intellectual property rights, before this technology can be widely adopted

for commercial use.

Overall, the research on the biosynthesis of quinine using biotechnology and synthetic biology

approaches is still in its early stages, and there is still much to be done to optimize the production and

commercialization of this valuable antimalarial drug. However, with continued research and

development, biotechnology and synthetic biology approaches have the potential to revolutionize the

production of quinine and improve access to this life-saving drug for people in need around the

world.

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5. References:

[1] K. G. R. K. &. B. U. C. Adhikari, " Biotechnological production of quinine: current status and future

prospects.," Applied Microbiology and Biotechnology, 103(2), 517-528., 2019.

[2] H. J. B. D. W. &. W. L. Böhm, "Biosynthesis of the quinoline alkaloids," Chemical Reviews, 104(2), 1039-

1072., 2004.

[3] V. &. L. P. De Luca, " The expanding universe of alkaloid biosynthesis.," Current Opinion in Plant Biology,

4(3), 225-233., 2001.

[4] V. M. &. F. D. A. Dubois, " Antimalarial drug resistance: modes of action and molecular basis of

resistance.," Journal of Global Infectious Diseases, 2(2), 114-122., 2010.

[5] A. L. G. &. Z. Y. Chiang, "Engineering non-native metabolic pathways for the biosynthesis of chemical

products.," Nature Reviews Chemistry, 3, 42-56., 2019.

[6] N. &. v. S. A. Kruger, "The oxidative pentose phosphate pathway: Structure and organisation.," Current

Opinion in Plant Biology, 6(3), 236-246., 2003.

[7] M. P. C. &. O. A. Moser, "Design and engineering of synthetic enzymatic pathways.," Current Opinion in

Chemical Biology, 49, 67-75., 2019.

[8] J. G. a. T. H. Milan R. Uskokovic, "Total synthesis of quinine and quinidine. I," ournal of the American

Chemical Society , 1970.

[9] A. C. M. &. G. F. Guzmán, "Quinine biosynthesis: Advances and challenges.," Frontiers in Bioengineering

and Biotechnology, 9, 654444., 2021.

[10] Y. D. D. &. K. P. Jaiswal, "Synthetic biology approaches for the biosynthesis of quinine and related

alkaloids: A review.," Frontiers in Bioengineering and Biotechnology,9, 721985., 2021.

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[11] S. &. K. J. Robinson, "Synthetic biology applications in the field of plant natural product biosynthesis,"

Journal of Experimental Botany, 71(3), 747-759., 2020.

[12] D. Ro, " Biosynthesis of plant-based medicinal compounds using synthetic biology.," Current Opinion in

Plant Biology, 31, 9-15., 2016.

[13] I. H. J. &. W. C. Müller, "The quinine biosynthesis trifecta: Biosynthesis, trafficking, and resistance.,"

Trends in Parasitology, 34(9), 747-758., 2018.

[14] http://dx.doi.org/10.1021/ja00704a036.

[15] R. B. W. a. W. E. Doering, "THE TOTAL SYNTHESIS OF QUININE1," Journal of the American Chemical

Society, 1944.

[16] R. B. W. a. W. E. Doering, "The Total Synthesis of Quinine," ournal of the American Chemical Society,

1945.

[17] a. C. S. a. R. M. Williams, "Rabe Rest in Peace: Confirmation of the Rabe–Kindler Conversion ofd-

Quinotoxine Into Quinine: Experimental Affirmation of theWoodward–Doering Formal Total Synthesis

of Quinine," Angewandte Chemie, 2008.

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