Production of acetyl-coenzyme a derived isoprenoids

1. A genetically modified yeast cell capable of producing an isoprenoid, the cell comprising:

(a) a nucleic acid encoding an NADH-using HMG-CoA reductase (HMGr) and optionally one or more heterologous nucleic acids encoding one or more enzymes of a mevalonate (MEV) pathway for making isopentenyl pyrophosphate;

(b) a heterologous nucleic acid encoding an acylating acetylaldehyde dehydrogenase (ADA, EC 1.2.1.10); and

(c) a functional disruption of one or more enzymes of the native pyruvate dehydrogenase (PDH)-bypass selected from the group consisting of acetyl-CoA synthetase 1 (ACS1), acetyl-CoA synthetase 2 (ACS2), and aldehyde dehydrogenase 6 (ALD6),

wherein the genetically modified yeast cell produces an increased amount of an isoprenoid compound compared to an yeast cell not comprising a heterologous nucleic acid sequence encoding said ADA.

2. The genetically modified host cell of claim 1 , wherein the one or more enzymes of the MEV pathway comprise an enzyme that condenses acetyl-CoA with malonyl-CoA to form acetoacetyl-CoA.

3. The genetically modified host cell of claim 1 , wherein the one or more enzymes of the MEV pathway comprise an acetyl-CoA:malonyl-CoA acyltransferase.

4. The genetically modified host cell of claim 1 , wherein the one or more enzymes of the MEV pathway comprise an NADH-using enzyme that converts 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) to mevalonate.

5. The genetically modified host cell of claim 1 , further comprising a heterologous nucleic acid encoding a phosphoketolase (PK).

6. The genetically modified host cell of claim 1 , further comprising a heterologous nucleic acid encoding a phosphotransacetylase (PTA).

7. The genetically modified host cell of claim 1 , wherein ACS1, ACS2 and ALD6 are functionally disrupted.

8. The genetically modified host cell of claim 1 , wherein the one or more enzymes of the MEV pathway comprise an enzyme that condenses two molecules of acetyl-CoA to form acetoacetyl-CoA.

9. The genetically modified host cell of claim 1 , wherein the one or more enzymes of the MEV pathway comprise an enzyme that condenses acetoacetyl-CoA with acetyl-CoA to form HMG-CoA.

10. The genetically modified host cell of claim 1 , wherein the one or more enzymes of the MEV pathway comprise an NADPH-using enzyme that converts HMG-CoA to mevalonate.

11. The genetically modified host cell of claim 1 , wherein the one or more enzymes of the MEV pathway comprise an enzyme that phosphorylates mevalonate to mevalonate 5-phosphate.

12. The genetically modified host cell of claim 1 , wherein the one or more enzymes of the MEV pathway comprise an enzyme that converts mevalonate 5-phosphate to mevalonate 5-pyrophosphate.

13. The genetically modified host cell of claim 1 , wherein the one or more enzymes of the MEV pathway comprise an enzyme that converts mevalonate 5-pyrophosphate to isopentenyl pyrophosphate.

14. The genetically modified host cell of claim 1 , wherein the one or more enzymes of the MEV pathway are selected from HMG-CoA synthase, mevalonate kinase, phosphomevalonate kinase and mevalonate pyrophosphate decarboxylase.

15. The genetically modified host cell of claim 1 , wherein the host cell comprises a plurality of heterologous nucleic acids encoding all of the enzymes of the MEV pathway.

16. The genetically modified host cell of claim 1 , wherein the one or more heterologous nucleic acids encoding one or more enzymes of the MEV pathway are under control of a single transcriptional regulator.

17. The genetically modified host cell of claim 1 , further comprising a heterologous nucleic acid encoding an enzyme that can convert isopentenyl pyrophosphate (IPP) into dimethylallyl pyrophosphate (DMAPP).

18. The genetically modified host cell of claim 1 , further comprising a heterologous nucleic acid encoding an enzyme that can condense IPP and/or DMAPP molecules to form a polyprenyl compound.

19. The genetically modified host cell of claim 1 , further comprising a heterologous nucleic acid encoding an enzyme that can modify IPP or a polyprenyl to form an isoprenoid compound.

20. The genetically modified host cell of claim 19 , wherein the enzyme that can modify IPP or a polyprenyl to form an isoprenoid compound is selected from the group consisting of carene synthase, geraniol synthase, linalool synthase, limonene synthase, myrcene synthase, ocimene synthase, α-pinene synthase, β-pinene synthase, γ-terpinene synthase, terpinolene synthase, amorphadiene synthase, α-farnesene synthase, β-farnesene synthase, farnesol synthase, nerolidol synthase, patchouliol synthase, nootkatone synthase, and abietadiene synthase.

21. The genetically modified host cell of claim 19 , wherein the isoprenoid is selected from the group consisting of a hemiterpene, monoterpene, diterpene, triterpene, tetraterpene, sesquiterpene, and polyterpene.

22. The genetically modified host cell of claim 19 , wherein the isoprenoid is a C 5 -C 20 isoprenoid.

23. The genetically modified host cell of claim 19 , wherein the isoprenoid is selected from the group consisting of abietadiene, amorphadiene, carene, α-farnesene, β-farnesene, farnesol, geraniol, geranylgeraniol, isoprene, linalool, limonene, myrcene, nerolidol, ocimene, patchoulol, β-pinene, sabinene, γ-terpinene, terpinolene, and valencene.

24. The genetically modified host cell of claim 1 , wherein the yeast is Saccharomyces cerevisiae.

25. A method for producing an isoprenoid comprising:

(a) culturing a population of the genetically modified yeast cell of claim 1 in a medium with a carbon source under conditions suitable for making said isoprenoid compound; and

(b) recovering said isoprenoid compound from the medium.

26. The method of claim 25 , wherein the genetically modified yeast cell produces an increased amount of an isoprenoid compound compared to the same genetically modified yeast cell not comprising a heterologous nucleotide sequence encoding said ADA.