Microorganisms for producing 1,4-butanediol and methods related thereto

Abstract

The invention provides non-naturally occurring microbial organisms comprising a 1,4-butanediol (BDO), 4-hydroxybutyryl-CoA, 4-hydroxybutanal or putrescine pathway comprising at least one exogenous nucleic acid encoding a BDO, 4-hydroxybutyryl-CoA, 4-hydroxybutanal or putrescine pathway enzyme expressed in a sufficient amount to produce BDO, 4-hydroxybutyryl-CoA, 4-hydroxybutanal or putrescine and further optimized for expression of BDO. The invention additionally provides methods of using such microbial organisms to produce BDO, 4-hydroxybutyryl-CoA, 4-hydroxybutanal or putrescine.

1 . A non-naturally occurring microbial organism, comprising a microbial organism having a 1,4-butanediol pathway comprising at least one exogenous nucleic acid encoding a 1,4-butanediol pathway enzyme expressed in a sufficient amount to produce 1,4-butanediol; said non-naturally occurring microbial organism further comprising:
 (i) a reductive TCA pathway comprising at least one exogenous nucleic acid encoding a reductive TCA pathway enzyme, wherein said at least one exogenous nucleic acid is selected from an ATP-citrate lyase, a citrate lyase, a citryl-CoA synthetase, a citryl-CoA lyase, a fumarate reductase, isocitrate dehydrogenase, and an alpha-ketoglutarate:ferredoxin oxidoreductase;   (ii) a reductive TCA pathway comprising at least one exogenous nucleic acid encoding a reductive TCA pathway enzyme, wherein said at least one exogenous nucleic acid is selected from a pyruvate:ferredoxin oxidoreductase, a phosphoenolpyruvate carboxylase, a phosphoenolpyruvate carboxykinase, a CO dehydrogenase, and an H 2  hydrogenase; or   (iii) at least one exogenous nucleic acid encodes an enzyme selected from a CO dehydrogenase, an H 2  hydrogenase, and combinations thereof;   wherein said 1,4-butanediol pathway comprises a pathway selected from:   (a) 4-hydroxybutanoate dehydrogenase, succinyl-CoA synthetase, CoA-dependent succinic semialdehyde dehydrogenase, and α-ketoglutarate decarboxylase;   (b) 4-hydroxybutanoate dehydrogenase, succinyl-CoA synthetase, CoA-dependent succinic semialdehyde dehydrogenase, 4-hydroxybutyrate:CoA transferase, 4-butyrate kinase, phosphotransbutyrylase, α-ketoglutarate decarboxylase, aldehyde dehydrogenase, alcohol dehydrogenase and an aldehyde/alcohol dehydrogenase;   (c) (i) an α-ketoglutarate decarboxylase, or an α-ketoglutarate dehydrogenase and a CoA-dependent succinic semialdehyde dehydrogenase, or a glutamate:succinate semialdehyde transaminase and a glutamate decarboxylase; (ii) a 4-hydroxybutanoate dehydrogenase; (iii) a 4-hydroxybutyryl-CoA:acetyl-CoA transferase, or a butyrate kinase and a phosphotransbutyrylase; (iv) an aldehyde dehydrogenase; and (v) an alcohol dehydrogenase;   (d) 4-aminobutyrate CoA transferase, 4-aminobutyryl-CoA hydrolase, 4-aminobutyrate-CoA ligase, 4-aminobutyryl-CoA oxidoreductase (deaminating), 4-aminobutyryl-CoA transaminase, and 4-hydroxybutyryl-CoA dehydrogenase;   (e) 4-aminobutyrate CoA transferase, 4-aminobutyryl-CoA hydrolase, 4-aminobutyrate-CoA ligase, 4-aminobutyryl-CoA reductase (alcohol forming), 4-aminobutyryl-CoA reductase, 4-aminobutan-1-ol dehydrogenase, 4-aminobutan-1-ol oxidoreductase (deaminating) and 4-aminobutan-1-ol transaminase;   (f) 4-aminobutyrate kinase, 4-aminobutyraldehyde dehydrogenase (phosphorylating), 4-aminobutan-1-ol dehydrogenase, 4-aminobutan-1-ol oxidoreductase (deaminating), 4-aminobutan-1-ol transaminase, [(4-aminobutanolyl)oxy]phosphonic acid oxidoreductase (deaminating), [(4-aminobutanolyl)oxy]phosphonic acid transaminase, 4-hydroxybutyryl-phosphate dehydrogenase, and 4-hydroxybutyraldehyde dehydrogenase (phosphorylating);   (g) alpha-ketoglutarate 5-kinase, 2,5-dioxopentanoic semialdehyde dehydrogenase (phosphorylating), 2,5-dioxopentanoic acid reductase, alpha-ketoglutarate CoA transferase, alpha-ketoglutaryl-CoA hydrolase, alpha-ketoglutaryl-CoA ligase, alpha-ketoglutaryl-CoA reductase, 5-hydroxy-2-oxopentanoic acid dehydrogenase, alpha-ketoglutaryl-CoA reductase (alcohol forming), 5-hydroxy-2-oxopentanoic acid decarboxylase, and 5-hydroxy-2-oxopentanoic acid dehydrogenase (decarboxylation);   (h) glutamate CoA transferase, glutamyl-CoA hydrolase, glutamyl-CoA ligase, glutamate 5-kinase, glutamate-5-semialdehyde dehydrogenase (phosphorylating), glutamyl-CoA reductase, glutamate-5-semialdehyde reductase, glutamyl-CoA reductase (alcohol forming), 2-amino-5-hydroxypentanoic acid oxidoreductase (deaminating), 2-amino-5-hydroxypentanoic acid transaminase, 5-hydroxy-2-oxopentanoic acid decarboxylase, 5-hydroxy-2-oxopentanoic acid dehydrogenase (decarboxylation);   (i) 3-hydroxybutyryl-CoA dehydrogenase, 3-hydroxybutyryl-CoA dehydratase, vinylacetyl-CoA Δ-isomerase, or 4-hydroxybutyryl-CoA dehydratase;   (j) homoserine deaminase, homoserine CoA transferase, homoserine-CoA hydrolase, homoserine-CoA ligase, homoserine-CoA deaminase, 4-hydroxybut-2-enoyl-CoA transferase, 4-hydroxybut-2-enoyl-CoA hydrolase, 4-hydroxybut-2-enoyl-CoA ligase, 4-hydroxybut-2-enoate reductase, 4-hydroxybutyryl-CoA transferase, 4-hydroxybutyryl-CoA hydrolase, 4-hydroxybutyryl-CoA ligase, or 4-hydroxybut-2-enoyl-CoA reductase;   (k) succinyl-CoA reductase (alcohol forming), 4-hydroxybutyryl-CoA hydrolase, 4-hydroxybutyryl-CoA ligase, or 4-hydroxybutanal dehydrogenase (phosphorylating);   (l) glutamate dehydrogenase, 4-aminobutyrate oxidoreductase (deaminating), 4-aminobutyrate transaminase, glutamate decarboxylase, 4-hydroxybutyryl-CoA hydrolase, 4-hydroxybutyryl-CoA ligase, or 4-hydroxybutanal dehydrogenase (phosphorylating);   (m) 4-aminobutyrate kinase; 4-aminobutyraldehyde dehydrogenase (phosphorylating); 4-aminobutan-1-ol dehydrogenase; and 4-aminobutan-1-ol oxidoreductase (deaminating) or 4-aminobutan-1-ol transaminase;   (n) 4-aminobutyrate kinase; [(4-aminobutanolyl)oxy]phosphonic acid oxidoreductase (deaminating) or [(4-aminobutanolyl)oxy]phosphonic acid transaminase; 4-hydroxybutyryl-phosphate dehydrogenase; and 4-hydroxybutyraldehyde dehydrogenase (phosphorylating);   (o) alpha-ketoglutarate CoA transferase, alpha-ketoglutaryl-CoA hydrolase, or alpha-ketoglutaryl-CoA ligase; alpha-ketoglutaryl-CoA reductase (alcohol forming); and 5-hydroxy-2-oxopentanoic acid decarboxylase;   (p) alpha-ketoglutarate CoA transferase, alpha-ketoglutaryl-CoA hydrolase, or alpha-ketoglutaryl-CoA ligase; alpha-ketoglutaryl-CoA reductase (alcohol forming); and 5-hydroxy-2-oxopentanoic acid dehydrogenase (decarboxylation);   (q) alpha-ketoglutarate 5-kinase; 2,5-dioxopentanoic semialdehyde dehydrogenase (phosphorylating); 2,5-dioxopentanoic acid reductase; and 5-hydroxy-2-oxopentanoic acid decarboxylase;   (r) alpha-ketoglutarate 5-kinase; 2,5-dioxopentanoic semialdehyde dehydrogenase (phosphorylating); 2,5-dioxopentanoic acid reductase; and 5-hydroxy-2-oxopentanoic acid dehydrogenase (decarboxylation);   (s) alpha-ketoglutarate CoA transferase, alpha-ketoglutaryl-CoA hydrolase, or alpha-ketoglutaryl-CoA ligase; alpha-ketoglutaryl-CoA reductase; 5-hydroxy-2-oxopentanoic acid dehydrogenase; and 5-hydroxy-2-oxopentanoic acid decarboxylase;   (t) alpha-ketoglutarate CoA transferase, alpha-ketoglutaryl-CoA hydrolase, or alpha-ketoglutaryl-CoA ligase; alpha-ketoglutaryl-CoA reductase; 5-hydroxy-2-oxopentanoic acid dehydrogenase; and 5-hydroxy-2-oxopentanoic acid dehydrogenase (decarboxylation);   (u) glutamate CoA transferase, glutamyl-CoA hydrolase, or glutamyl-CoA ligase; glutamyl-CoA reductase (alcohol forming); 2-amino-5-hydroxypentanoic acid oxidoreductase (deaminating) or 2-amino-5-hydroxypentanoic acid transaminase; and 5-hydroxy-2-oxopentanoic acid decarboxylase or 5-hydroxy-2-oxopentanoic acid dehydrogenase (decarboxylation);   (v) glutamate 5-kinase; glutamate-5-semialdehyde dehydrogenase (phosphorylating); 2-amino-5-hydroxypentanoic acid oxidoreductase (deaminating) or 2-amino-5-hydroxypentanoic acid transaminase; and 5-hydroxy-2-oxopentanoic acid decarboxylase or 5-hydroxy-2-oxopentanoic acid dehydrogenase (decarboxylation);   (w) glutamate CoA transferase, glutamyl-CoA hydrolase, or glutamyl-CoA ligase; glutamyl-CoA reductase; glutamate-5-semialdehyde reductase; 2-amino-5-hydroxypentanoic acid oxidoreductase (deaminating) or 2-amino-5-hydroxypentanoic acid transaminase; and 5-hydroxy-2-oxopentanoic acid decarboxylase or 5-hydroxy-2-oxopentanoic acid dehydrogenase (decarboxylation);   (x) glutamate 5-kinase; glutamate-5-semialdehyde dehydrogenase (phosphorylating); glutamate-5-semialdehyde reductase; 2-amino-5-hydroxypentanoic acid oxidoreductase (deaminating) or 2-amino-5-hydroxypentanoic acid transaminase; and 5-hydroxy-2-oxopentanoic acid decarboxylase or 5-hydroxy-2-oxopentanoic acid dehydrogenase (decarboxylation);   (y) homoserine deaminase; 4-hydroxybut-2-enoyl-CoA transferase, 4-hydroxybut-2-enoyl-CoA hydrolase, 4-hydroxybut-2-enoyl-CoA ligase; 4-hydroxybut-2-enoyl-CoA reductase;   (z) homoserine CoA transferase, homoserine-CoA hydrolase, or homoserine-CoA ligase; homoserine-CoA deaminase; and 4-hydroxybut-2-enoyl-CoA reductase;   (aa) homoserine deaminase; 4-hydroxybut-2-enoate reductase; and 4-hydroxybutyryl-CoA transferase, 4-hydroxybutyryl-CoA hydrolase, or 4-hydroxybutyryl-CoA ligase;   (bb) (i) alpha-ketoglutarate decarboxylase; or alpha-ketoglutarate dehydrogenase and CoA-dependent succinate semialdehyde dehydrogenase; or glutamate:succinate semialdehyde transaminase and glutamate decarboxylase; (ii) 4-hydroxybutyrate dehydrogenase; (iii) 4-hydroxybutyryl-CoA transferase; or 4-hydroxybutyrate kinase and phosphotrans-4-hydroxybutyrylase; (iv) 4-hydroxybutyryl-CoA reductase; and (v) 4-hydroxybutyraldehyde reductase; or aldehyde/alcohol dehydrogenase;   (cc) (i) alpha-ketoglutarate decarboxylase; or succinyl-CoA synthetase and CoA-dependent succinate semialdehyde dehydrogenase; (ii) 4-hydroxybutyrate dehydrogenase; (iii) 4-hydroxybutyryl-CoA transferase; or 4-hydroxybutyrate kinase and phosphotrans-4-hydroxybutyrylase; and (iv) aldehyde dehydrogenase; and alcohol dehydrogenase; or aldehyde/alcohol dehydrogenase;   (dd) (i) alpha-ketoglutarate decarboxylase; or glutamate dehydrogenase; glutamate decarboxylase; and deaminating 4-aminobutyrate oxidoreductase or 4-aminobutyrate transaminase; or alpha-ketoglutarate dehydrogenase and CoA-dependent succinate semialdehyde dehydrogenase; (ii) 4-hydroxybutyrate dehydrogenase; and (iii) 4-hydroxybutyrate kinase; phosphotrans-4-hydroxybutyrylase; 4-hydroxybutyryl-CoA reductase; and 4-hydroxybutyraldehyde reductase; or 4-hydroxybutyrate kinase; phosphorylating 4-hydroxybutanal dehydrogenase; and 4-hydroxybutyraldehyde reductase; or 4-hydroxybutyrate kinase; phosphotrans-4-hydroxybutyrylase; and alcohol forming 4-hydroxybutyryl-CoA reductase; or 4-hydroxybutyryl-CoA transferase or 4-hydroxybutyryl-CoA hydrolase or 4-hydroxybutyryl-CoA ligase; 4-hydroxybutyryl-CoA reductase; and 4-hydroxybutyraldehyde reductase; or 4-hydroxybutyryl-CoA transferase or 4-hydroxybutyryl-CoA hydrolase or 4-hydroxybutyryl-CoA ligase; and alcohol forming 4-hydroxybutyryl-CoA reductase;   (ee) (i) glutamate CoA transferase or glutamyl-CoA hydrolase or glutamyl-CoA ligase; glutamyl-CoA reductase; and glutamate-5-semialdehyde reductase; or glutamate CoA transferase or glutamyl-CoA hydrolase or glutamyl-CoA ligase; and alcohol forming glutamyl-CoA reductase; or glutamate 5-kinase; phosphorylating glutamate-5-semialdehyde dehydrogenase; and glutamate-5-semialdehyde reductase; (ii) deaminating 2-amino-5-hydroxypentanoic acid oxidoreductase or 2-amino-5-hydroxypentanoic acid transaminase; and (iii) 5-hydroxy-2-oxopentanoic acid decarboxylase; and 4-hydroxybutyraldehyde reductase; or decarboxylating 5-hydroxy-2-oxopentanoic acid dehydrogenase; 4-hydroxybutyryl-CoA reductase; and 4-hydroxybutyraldehyde reductase; or decarboxylating 5-hydroxy-2-oxopentanoic acid dehydrogenase and alcohol forming 4-hydroxybutyryl-CoA reductase;   (ff) succinyl-CoA reductase (aldehyde forming); 4-hydroxybutyrate dehydrogenase; and 4-hydroxybutyrate reductase; and optionally 1,4-butandiol dehydrogenase;   (gg) alpha-ketoglutarate decarboxylase; 4-hydroxybutyrate dehydrogenase; and 4-hydroxybutyrate reductase; and optionally 1,4-butandiol dehydrogenase;   (hh) succinate reductase; 4-hydroxybutyrate dehydrogenase, and 4-hydroxybutyrate reductase; and optionally 1,4-butandiol dehydrogenase;   (ii) alpha-ketoglutarate decarboxylase, or glutamate dehydrogenase or glutamate transaminase and glutamate decarboxylase and 4-aminobutyrate dehydrogenase or 4-aminobutyrate transaminase; 4-hydroxybutyrate dehydrogenase; and 4-hydroxybutyrate reductase; and optionally 1,4-butandiol dehydrogenase;   (jj) alpha-ketoglutarate reductase; 5-hydroxy-2-oxopentanoate dehydrogenase; and 5-hydroxy-2-oxopentanoate decarboxylase; and optionally 1,4-butandiol dehydrogenase;   (kk) Acetoacetyl-CoA thiolase or acetoacetyl-CoA synthase; 3-Hydroxybutyryl-CoA dehydrogenase; Crotonase; Crotonyl-CoA hydratase; and 4-hydroxybutyryl-CoA reductase (alcohol forming);   (ll) Acetoacetyl-CoA thiolase or acetoacetyl-CoA synthase; 3-Hydroxybutyryl-CoA dehydrogenase; Crotonase; Crotonyl-CoA hydratase; 4-hydroxybutyryl-CoA reductase (aldehyde forming); and 1,4-butanediol dehydrogenase;   (mm) Acetoacetyl-CoA thiolase or acetoacetyl-CoA synthase; 3-Hydroxybutyryl-CoA dehydrogenase; Crotonase; Crotonyl-CoA hydratase; 4-Hydroxybutyryl-CoA transferase, 4-Hydroxybutyryl-CoA synthetase, 4-Hydroxybutyryl-CoA hydrolase, or Phosphotrans-4-hydroxybutyrylase/4-Hydroxybutyrate kinase; 4-Hydroxybutyrate reductase; and 1,4-butanediol dehydrogenase;   (nn) Succinate reductase; 4-Hydroxybutyrate dehydrogenase; 4-Hydroxybutyrate kinase; Phosphotrans-4-hydroxybutyrylasel; 4-Hydroxybutyryl-CoA reductase (aldehyde forming); and 1,4-butanediol dehydrogenase;   (oo) Succinate reductase; 4-Hydroxybutyrate dehydrogenase; 4-Hydroxybutyrate kinase; 4-Hydroxybutyryl-phosphate reductase; and 1,4-butanediol dehydrogenase;   (pp) Succinate reductase; 4-Hydroxybutyrate dehydrogenase; 4-Hydroxybutyrate reductase; and 1,4-butanediol dehydrogenase;   (qq) Succinate reductase; 4-Hydroxybutyrate dehydrogenase; 4-Hydroxybutyryl-CoA transferase, or 4-Hydroxybutyryl-CoA synthetase; and 4-Hydroxybutyryl-CoA reductase (alcohol forming);   (rr) Succinate reductase; 4-Hydroxybutyrate dehydrogenase; 4-Hydroxybutyryl-CoA transferase, or 4-Hydroxybutyryl-CoA synthetase; 4-Hydroxybutyryl-CoA reductase (aldehyde forming); and 1,4-butanediol dehydrogenase;   (ss) Succinate reductase; 4-Hydroxybutyrate dehydrogenase; 4-Hydroxybutyrate kinase; Phosphotrans-4-hydroxybutyrylase; and 4-Hydroxybutyryl-CoA reductase (alcohol forming);   (tt) Succinyl-CoA transferase, or Succinyl-CoA synthetase (or succinyl-CoA ligase); Succinyl-CoA reductase (aldehyde forming); 4-Hydroxybutyrate dehydrogenase; 4-Hydroxybutyrate kinase; Phosphotrans-4-hydroxybutyrylase; 4-Hydroxybutyryl-CoA reductase (aldehyde forming); and 1,4-butanediol dehydrogenase;   (uu) Succinyl-CoA transferase, or Succinyl-CoA synthetase (or succinyl-CoA ligase); Succinyl-CoA reductase (aldehyde forming); 4-Hydroxybutyrate dehydrogenase; 4-Hydroxybutyrate kinase; 4-Hydroxybutyryl-phosphate reductase; and 1,4-butanediol dehydrogenase;   (vv) Succinyl-CoA transferase, or Succinyl-CoA synthetase (or succinyl-CoA ligase); Succinyl-CoA reductase (aldehyde forming); 4-Hydroxybutyrate dehydrogenase; 4-Hydroxybutyrate reductase; and 1,4-butanediol dehydrogenase;   (ww) Succinyl-CoA transferase, or Succinyl-CoA synthetase (or succinyl-CoA ligase); Succinyl-CoA reductase (aldehyde forming); 4-Hydroxybutyrate dehydrogenase; 4-Hydroxybutyryl-CoA transferase, or 4-Hydroxybutyryl-CoA synthetase; and 4-Hydroxybutyryl-CoA reductase (alcohol forming);   (xx) Succinyl-CoA transferase, or Succinyl-CoA synthetase (or succinyl-CoA ligase); Succinyl-CoA reductase (aldehyde forming); 4-Hydroxybutyrate dehydrogenase; 4-Hydroxybutyryl-CoA transferase, or 4-Hydroxybutyryl-CoA synthetase; 4-Hydroxybutyryl-CoA reductase (aldehyde forming); and 1,4-butanediol dehydrogenase;   (yy) Succinyl-CoA transferase, or Succinyl-CoA synthetase (or succinyl-CoA ligase); Succinyl-CoA reductase (aldehyde forming); 4-Hydroxybutyrate dehydrogenase; 4-Hydroxybutyrate kinase; Phosphotrans-4-hydroxybutyrylase; and 4-Hydroxybutyryl-CoA reductase (alcohol forming);   (zz) Alpha-ketoglutarate decarboxylase or (Glutamate dehydrogenase and/or Glutamate transaminase; Glutamate decarboxylase; 4-aminobutyrate dehydrogenase and/or 4-aminobutyrate transaminase); 4-Hydroxybutyrate dehydrogenase; 4-Hydroxybutyrate kinase; Phosphotrans-4-hydroxybutyrylase; 4-Hydroxybutyryl-CoA reductase (aldehyde forming); and 1,4-butanediol dehydrogenase;   (aaa) Alpha-ketoglutarate decarboxylase or (Glutamate dehydrogenase and/or Glutamate transaminase; Glutamate decarboxylase; 4-aminobutyrate dehydrogenase and/or 4-aminobutyrate transaminase); 4-Hydroxybutyrate dehydrogenase; 4-Hydroxybutyrate kinase; 4-Hydroxybutyryl-phosphate reductase; and 1,4-butanediol dehydrogenase;   (bbb) Alpha-ketoglutarate decarboxylase or (Glutamate dehydrogenase and/or Glutamate transaminase; Glutamate decarboxylase; 4-aminobutyrate dehydrogenase and/or 4-aminobutyrate transaminase); 4-Hydroxybutyrate dehydrogenase; 4-Hydroxybutyrate reductase; and 1,4-butanediol dehydrogenase;   (ccc) Alpha-ketoglutarate decarboxylase or (Glutamate dehydrogenase and/or Glutamate transaminase; Glutamate decarboxylase; 4-aminobutyrate dehydrogenase and/or 4-aminobutyrate transaminase); 4-Hydroxybutyrate dehydrogenase; 4-Hydroxybutyryl-CoA transferase, or 4-Hydroxybutyryl-CoA synthetase; and 4-Hydroxybutyryl-CoA reductase (alcohol forming);   (ddd) Alpha-ketoglutarate decarboxylase or (Glutamate dehydrogenase and/or Glutamate transaminase; Glutamate decarboxylase; 4-aminobutyrate dehydrogenase and/or 4-aminobutyrate transaminase); 4-Hydroxybutyrate dehydrogenase; 4-Hydroxybutyryl-CoA transferase, or 4-Hydroxybutyryl-CoA synthetase; 4-Hydroxybutyryl-CoA reductase (aldehyde forming); and 1,4-butanediol dehydrogenase;   (eee) Alpha-ketoglutarate decarboxylase or (Glutamate dehydrogenase and/or Glutamate transaminase; Glutamate decarboxylase; 4-aminobutyrate dehydrogenase and/or 4-aminobutyrate transaminase); 4-Hydroxybutyrate dehydrogenase; 4-Hydroxybutyrate kinase; Phosphotrans-4-hydroxybutyrylase; and 4-Hydroxybutyryl-CoA reductase (alcohol forming);   (fff) Succinyl-CoA transferase, or Succinyl-CoA synthetase (or succinyl-CoA ligase); Succinyl-CoA reductase (alcohol forming); 4-Hydroxybutyrate kinase; Phosphotrans-4-hydroxybutyrylase; 4-Hydroxybutyryl-CoA reductase (aldehyde forming); and 1,4-butanediol dehydrogenase;   (ggg) Succinyl-CoA transferase, or Succinyl-CoA synthetase (or succinyl-CoA ligase); Succinyl-CoA reductase (alcohol forming); 4-Hydroxybutyrate kinase; 4-Hydroxybutyryl-phosphate reductase; and 1,4-butanediol dehydrogenase;   (hhh) Succinyl-CoA transferase, or Succinyl-CoA synthetase (or succinyl-CoA ligase); Succinyl-CoA reductase (alcohol forming); 4-Hydroxybutyrate reductase; and 1,4-butanediol dehydrogenase;   (iii) Succinyl-CoA transferase, or Succinyl-CoA synthetase (or succinyl-CoA ligase); Succinyl-CoA reductase (alcohol forming); 4-Hydroxybutyryl-CoA transferase, or 4-Hydroxybutyryl-CoA synthetase; and 4-Hydroxybutyryl-CoA reductase (alcohol forming);   (jjj) Succinyl-CoA transferase, or Succinyl-CoA synthetase (or succinyl-CoA ligase); Succinyl-CoA reductase (alcohol forming); 4-Hydroxybutyryl-CoA transferase, or 4-Hydroxybutyryl-CoA synthetase; 4-Hydroxybutyryl-CoA reductase (aldehyde forming); and 1,4-butanediol dehydrogenase;   (kkk) Succinyl-CoA transferase, or Succinyl-CoA synthetase (or succinyl-CoA ligase); Succinyl-CoA reductase (alcohol forming); 4-Hydroxybutyrate kinase; Phosphotrans-4-hydroxybutyrylase; and 4-Hydroxybutyryl-CoA reductase (alcohol forming); and   (lll) any of the pathways that produce 1,4-butanediol as shown in any of  FIG. 1 ,  8 - 13 ,  58 ,  62 ,  63  or  72 - 74 .   
     
     
         2 . The non-naturally occurring microbial organism of  claim 1 , wherein said microbial organism comprising (i) further comprises an exogenous nucleic acid encoding an enzyme selected from a pyruvate:ferredoxin oxidoreductase, an aconitase, a succinyl-CoA synthetase, a succinyl-CoA transferase, a fumarase, a malate dehydrogenase, an acetate kinase, a phosphotransacetylase, an acetyl-CoA synthetase, an NAD(P)H:ferredoxin oxidoreductase, ferredoxin, and combinations thereof. 
     
     
         3 . The non-naturally occurring microbial organism of  claim 1 , wherein said microbial organism comprising (ii) further comprises an exogenous nucleic acid encoding an enzyme selected from an aconitase, an isocitrate dehydrogenase, a succinyl-CoA synthetase, a succinyl-CoA transferase, a fumarase, a malate dehydrogenase, NAD(P):ferredoxin oxidoreductase, ferredoxin, and combinations thereof. 
     
     
         4 . The non-naturally occurring microbial organism of  claim 1 , wherein said microbial organism comprising (iii) further comprises an exogenous nucleic acid encoding an enzyme selected from NAD(P):ferredoxin oxidoreductase and ferredoxin. 
     
     
         5 - 6 . (canceled) 
     
     
         7 . The non-naturally occurring microbial organism of  claim 1 , wherein said microbial organism:
 (i) comprising pathways (a), (b) or (c) further comprises an enzyme selected from succinyl-CoA synthetase, exogenous CoA-dependent succinic semialdehyde dehydrogenase or exogenous succinyl-CoA synthetase and exogenous CoA-dependent succinic semialdehyde dehydrogenase;   (ii) comprising pathway (d), (g), (h), (i), (j) further comprises an enzyme selected from 4-hydroxybutyryl-CoA reductase (alcohol forming), 4-hydroxybutyryl-CoA reductase, or 1,4-butanediol dehydrogenase;   (iii) comprising pathway (e) or (f) further comprises 1,4-butanediol dehydrogenase;   (iv) comprising pathway (k) further comprises succinyl-CoA reductase, 4-hydroxybutyrate dehydrogenase, 4-hydroxybutyryl-CoA transferase, 4-hydroxybutyrate kinase, phosphotrans-4-hydroxybutyrylase, 4-hydroxybutyryl-CoA reductase, 4-hydroxybutyryl-CoA reductase (alcohol forming), or 1,4-butanediol dehydrogenase;   (v) comprising pathway (1) further comprises alpha-ketoglutarate decarboxylase, 4-hydroxybutyrate dehydrogenase, 4-hydroxybutyryl-CoA transferase, 4-hydroxybutyrate kinase, phosphotrans-4-hydroxybutyrylase, 4-hydroxybutyryl-CoA reductase, 4-hydroxybutyryl-CoA reductase (alcohol forming), or 1,4-butanediol dehydrogenase.   
     
     
         8 . The non-naturally occurring microbial organism of  claim 1 , wherein said microbial organism comprises two, three, four or five exogenous nucleic acids each encoding enzymes of (i), (ii) or (iii). 
     
     
         9 . The non-naturally occurring microbial organism of  claim 8 , wherein said microbial organism comprising (i) comprises three exogenous nucleic acids encoding ATP-citrate lyase or citrate lyase, a fumarate reductase, and an alpha-ketoglutarate:ferredoxin oxidoreductase;
 wherein said microbial organism comprising (ii) comprises five exogenous nucleic acids encoding pyruvate:ferredoxin oxidoreductase, a phosphoenolpyruvate carboxylase, a phosphoenolpyruvate carboxykinase, a CO dehydrogenase, and an H 2  hydrogenase; or   wherein said microbial organism comprising (iii) comprises two exogenous nucleic acids encoding CO dehydrogenase and H 2  hydrogenase.   
     
     
         10 . (canceled) 
     
     
         11 . A method for producing 1,4-butanediol, comprising culturing the non-naturally occurring microbial organism of  claim 1  under conditions and for a sufficient period of time to produce 1,4-butanediol. 
     
     
         12 . A non-naturally occurring microbial organism, comprising a microbial organism having a 4-hydroxybutyrate pathway comprising at least one exogenous nucleic acid encoding a 4-hydroxybutyrate pathway enzyme 4-hydroxybutyrate expressed in a sufficient amount to produce 4-hydroxybutyrate; said non-naturally occurring microbial organism further comprising:
 (i) a reductive TCA pathway comprising at least one exogenous nucleic acid encoding a reductive TCA pathway enzyme, wherein said at least one exogenous nucleic acid is selected from an ATP-citrate lyase, citrate lyase, a citryl-CoA synthetase, a citryl-CoA lyase, a fumarate reductase, isocitrate dehydrogenase and an alpha-ketoglutarate:ferredoxin oxidoreductase;   (ii) a reductive TCA pathway comprising at least one exogenous nucleic acid encoding a reductive TCA pathway enzyme, wherein said at least one exogenous nucleic acid is selected from a pyruvate:ferredoxin oxidoreductase, a phosphoenolpyruvate carboxylase, a phosphoenolpyruvate carboxykinase, a CO dehydrogenase, and an H 2  hydrogenase; or   (iii) at least one exogenous nucleic acid encodes an enzyme selected from a CO dehydrogenase, an H 2  hydrogenase, and combinations thereof;   (a) Acetoacetyl-CoA thiolase or acetoacetyl-CoA synthase; 3-Hydroxybutyryl-CoA dehydrogenase; Crotonase; Crotonyl-CoA hydratase; and 4-Hydroxybutyryl-CoA transferase, 4-Hydroxybutyryl-CoA synthetase, 4-Hydroxybutyryl-CoA hydrolase, or Phosphotrans-4-hydroxybutyrylase/4-Hydroxybutyrate kinase;   (b) Acetoacetyl-CoA thiolase or acetoacetyl-CoA synthase; 3-Hydroxybutyryl-CoA dehydrogenase; Crotonase; Crotonyl-CoA hydratase; and 4-Hydroxybutyryl-CoA transferase, hydrolase or synthetase;   (c) Acetoacetyl-CoA thiolase or acetoacetyl-CoA synthase; 3-Hydroxybutyryl-CoA dehydrogenase; Crotonase; Crotonyl-CoA hydratase; Phosphotrans-4-hydroxybutyrylase; and 4-Hydroxybutyrate kinase;   (d) Succinate reductase; and 4-Hydroxybutyrate dehydrogenase;   (e) Succinyl-CoA transferase, or Succinyl-CoA synthetase (or succinyl-CoA ligase); Succinyl-CoA reductase (aldehyde forming); and 4-Hydroxybutyrate dehydrogenase;   (f) Alpha-ketoglutarate decarboxylase or (Glutamate dehydrogenase and/or Glutamate transaminase; Glutamate decarboxylase; 4-aminobutyrate dehydrogenase and/or 4-aminobutyrate transaminase); and 4-Hydroxybutyrate dehydrogenase;   (g) Succinyl-CoA transferase, or Succinyl-CoA synthetase (or succinyl-CoA ligase); and Succinyl-CoA reductase (alcohol forming);   (h) acetoacetyl-CoA thiolase or acetoacetyl-CoA synthase, a 3-hydroxybutyryl-CoA dehydrogenase, a crotonase, a crotonyl-CoA hydratase, a 4-hydroxybutyryl-CoA transferase, a phosphotrans-4-hydroxybutyrylase, and a 4-hydroxybutyrate kinase;   (i) 4-hydroxybutanoate dehydrogenase, succinyl-CoA synthetase, CoA-dependent succinic semialdehyde dehydrogenase, and α-ketoglutarate decarboxylase;   (j) (i) an α-ketoglutarate decarboxylase, or an α-ketoglutarate dehydrogenase and a CoA-dependent succinic semialdehyde dehydrogenase, or a glutamate:succinate semialdehyde transaminase and a glutamate decarboxylase; (ii) a 4-hydroxybutanoate dehydrogenase;   (k) succinyl-CoA reductase (alcohol forming), 4-hydroxybutyryl-CoA hydrolase, 4-hydroxybutyryl-CoA ligase, or 4-hydroxybutanal dehydrogenase (phosphorylating);   (l) glutamate dehydrogenase, 4-aminobutyrate oxidoreductase (deaminating), 4-aminobutyrate transaminase, glutamate decarboxylase, 4-hydroxybutyryl-CoA hydrolase, 4-hydroxybutyryl-CoA ligase, or 4-hydroxybutanal dehydrogenase (phosphorylating);   (m) homoserine deaminase; 4-hydroxybut-2-enoyl-CoA transferase, 4-hydroxybut-2-enoyl-CoA hydrolase, 4-hydroxybut-2-enoyl-CoA ligase; 4-hydroxybut-2-enoyl-CoA reductase;   (n) homoserine CoA transferase, homoserine-CoA hydrolase, or homoserine-CoA ligase; homoserine-CoA deaminase; and 4-hydroxybut-2-enoyl-CoA reductase;   (o) homoserine deaminase; 4-hydroxybut-2-enoate reductase; and 4-hydroxybutyryl-CoA transferase, 4-hydroxybutyryl-CoA hydrolase, or 4-hydroxybutyryl-CoA ligase;   (p) succinyl-CoA reductase (aldehyde forming); and 4-hydroxybutyrate dehydrogenase;   (q) alpha-ketoglutarate decarboxylase; and 4-hydroxybutyrate dehydrogenase;   (r) succinate reductase; and 4-hydroxybutyrate dehydrogenase;   (s) alpha-ketoglutarate decarboxylase, or glutamate dehydrogenase or glutamate transaminase and glutamate decarboxylase and 4-aminobutyrate dehydrogenase or 4-aminobutyrate transaminase; and 4-hydroxybutyrate dehydrogenase; and   (t) a 4-hydroxybutyrate pathway selected from any of the pathways that produce 4-hydroxybutyrate as shown in any of  FIG. 1 ,  8 - 13 ,  58 ,  62 ,  63  or  72 - 74 .   
     
     
         13 . The non-naturally occurring microbial organism of  claim 12 , wherein said microbial organism comprising (i) further comprises an exogenous nucleic acid encoding an enzyme selected from a pyruvate:ferredoxin oxidoreductase, an aconitase, a succinyl-CoA synthetase, a succinyl-CoA transferase, a fumarase, a malate dehydrogenase, an acetate kinase, a phosphotransacetylase, an acetyl-CoA synthetase, an NAD(P)H:ferredoxin oxidoreductase, ferredoxin, and combinations thereof. 
     
     
         14 . The non-naturally occurring microbial organism of  claim 12 , wherein said microbial organism comprising (ii) further comprises an exogenous nucleic acid encoding an enzyme selected from an aconitase, an isocitrate dehydrogenase, a succinyl-CoA synthetase, a succinyl-CoA transferase, a fumarase, a malate dehydrogenase, NAD(P):ferredoxin oxidoreductase, ferredoxin, and combinations thereof. 
     
     
         15 . The non-naturally occurring microbial organism of  claim 12 , wherein said microbial organism comprising (iii) further comprises an exogenous nucleic acid encoding an enzyme selected from NAD(P):ferredoxin oxidoreductase and ferredoxin. 
     
     
         16 - 18 . (canceled) 
     
     
         19 . The non-naturally occurring microbial organism of claim  18 , wherein said microbial organism comprising (i) comprises three exogenous nucleic acids encoding ATP-citrate lyase or citrate lyase, a fumarate reductase, and an alpha-ketoglutarate:ferredoxin oxidoreductase;
 wherein said microbial organism comprising (ii) comprises five exogenous nucleic acids encoding pyruvate:ferredoxin oxidoreductase, a phosphoenolpyruvate carboxylase, a phosphoenolpyruvate carboxykinase, a CO dehydrogenase, and an H 2  hydrogenase; or   wherein said microbial organism comprising (iii) comprises two exogenous nucleic acids encoding CO dehydrogenase and H 2  hydrogenase.   
     
     
         20 . (canceled) 
     
     
         21 . A method for producing 4-hydroxybutyrate, comprising culturing the non-naturally occurring microbial organism of  claim 12  under conditions and for a sufficient period of time to produce 4-hydroxybutyrate. 
     
     
         22 . A non-naturally occurring microbial organism, comprising a microbial organism having a gamma-butyrolactone pathway comprising at least one exogenous nucleic acid encoding a gamma-butyrolactone pathway enzyme expressed in a sufficient amount to produce gamma-butyrolactone; said non-naturally occurring microbial organism further comprising:
 (i) a reductive TCA pathway comprising at least one exogenous nucleic acid encoding a reductive TCA pathway enzyme, wherein said at least one exogenous nucleic acid is selected from an ATP-citrate lyase, citrate lyase, a citryl-CoA synthetase, a citryl-CoA lyase, a fumarate reductase, isocitrate dehydrogenase and an alpha-ketoglutarate:ferredoxin oxidoreductase;   (ii) a reductive TCA pathway comprising at least one exogenous nucleic acid encoding a reductive TCA pathway enzyme, wherein said at least one exogenous nucleic acid is selected from a pyruvate:ferredoxin oxidoreductase, a phosphoenolpyruvate carboxylase, a phosphoenolpyruvate carboxykinase, a CO dehydrogenase, and an H 2  hydrogenase; or   (iii) at least one exogenous nucleic acid encodes an enzyme selected from a CO dehydrogenase, an H 2  hydrogenase, and combinations thereof;   (a) Acetoacetyl-CoA thiolase or acetoacetyl-CoA synthase; 3-Hydroxybutyryl-CoA dehydrogenase; Crotonase; Crotonyl-CoA hydratase; and spontaneous or enzyme catalyzed;   (b) Acetoacetyl-CoA thiolase or acetoacetyl-CoA synthase; 3-Hydroxybutyryl-CoA dehydrogenase; Crotonase; Crotonyl-CoA hydratase; Phosphotrans-4-hydroxybutyrylase; amd spontaneous or enzyme catalyzed;   (c) Succinate reductase; 4-Hydroxybutyrate dehydrogenase; 4-Hydroxybutyrate kinase; Phosphotrans-4-hydroxybutyrylase; and 4-Hydroxybutyryl-CoA hydrolase or spontaneous;   (d) Succinate reductase; 4-Hydroxybutyrate dehydrogenase; 4-Hydroxybutyryl-CoA transferase, or 4-Hydroxybutyryl-CoA synthetase; and 4-Hydroxybutyryl-CoA hydrolase or spontaneous;   (e) Succinyl-CoA transferase, or Succinyl-CoA synthetase (or succinyl-CoA ligase); Succinyl-CoA reductase (aldehyde forming); 4-Hydroxybutyrate dehydrogenase; 4-Hydroxybutyrate kinase; Phosphotrans-4-hydroxybutyrylase; and 4-Hydroxybutyryl-CoA hydrolase or spontaneous;   (f) Succinyl-CoA transferase, or Succinyl-CoA synthetase (or succinyl-CoA ligase); Succinyl-CoA reductase (aldehyde forming); 4-Hydroxybutyrate dehydrogenase; 4-Hydroxybutyryl-CoA transferase, or 4-Hydroxybutyryl-CoA synthetase; 4-Hydroxybutyryl-CoA hydrolase or spontaneous;   (g) Alpha-ketoglutarate decarboxylase or (Glutamate dehydrogenase and/or Glutamate transaminase; Glutamate decarboxylase; 4-aminobutyrate dehydrogenase and/or 4-aminobutyrate transaminase); 4-Hydroxybutyrate dehydrogenase; 4-Hydroxybutyrate kinase; Phosphotrans-4-hydroxybutyrylase; and 4-Hydroxybutyryl-CoA hydrolase or spontaneous;   (h) Alpha-ketoglutarate decarboxylase or (Glutamate dehydrogenase and/or Glutamate transaminase; Glutamate decarboxylase; 4-aminobutyrate dehydrogenase and/or 4-aminobutyrate transaminase); 4-Hydroxybutyrate dehydrogenase; 4-Hydroxybutyryl-CoA transferase, or 4-Hydroxybutyryl-CoA synthetase; and 4-Hydroxybutyryl-CoA hydrolase or spontaneous;   (i) Succinyl-CoA transferase, or Succinyl-CoA synthetase (or succinyl-CoA ligase); Succinyl-CoA reductase (alcohol forming); 4-Hydroxybutyrate kinase; Phosphotrans-4-hydroxybutyrylase; 4-Hydroxybutyryl-CoA hydrolase or spontaneous;   (j) Succinyl-CoA transferase, or Succinyl-CoA synthetase (or succinyl-CoA ligase); Succinyl-CoA reductase (alcohol forming); 4-Hydroxybutyryl-CoA transferase, or 4-Hydroxybutyryl-CoA synthetase; and 4-Hydroxybutyryl-CoA hydrolase or spontaneous;   (k) alpha-ketoglutarate reductase; 5-hydroxy-2-oxopentanoate dehydrogenase; and 5-hydroxy-2-oxopentanoate dehydrogenase (decarboxylation)   (l) 4-hydroxybutanoate dehydrogenase, succinyl-CoA synthetase, CoA-dependent succinic semialdehyde dehydrogenase, and α-ketoglutarate decarboxylase;   (m) 4-hydroxybutanoate dehydrogenase, succinyl-CoA synthetase, CoA-dependent succinic semialdehyde dehydrogenase, 4-hydroxybutyrate:CoA transferase, 4-butyrate kinase, phosphotransbutyrylase, α-ketoglutarate decarboxylase;   (n) (i) an α-ketoglutarate decarboxylase, or an α-ketoglutarate dehydrogenase and a CoA-dependent succinic semialdehyde dehydrogenase, or a glutamate:succinate semialdehyde transaminase and a glutamate decarboxylase; (ii) a 4-hydroxybutanoate dehydrogenase; (iii) a 4-hydroxybutyryl-CoA:acetyl-CoA transferase, or a butyrate kinase and a phosphotransbutyrylase;   (o) 4-aminobutyrate CoA transferase, 4-aminobutyryl-CoA hydrolase, 4-aminobutyrate-CoA ligase, 4-aminobutyryl-CoA oxidoreductase (deaminating), 4-aminobutyryl-CoA transaminase, and 4-hydroxybutyryl-CoA dehydrogenase;   (p) 4-aminobutyrate CoA transferase, 4-aminobutyryl-CoA hydrolase, 4-aminobutyrate-CoA ligase, 4-aminobutyryl-CoA reductase (alcohol forming), 4-aminobutyryl-CoA reductase, 4-aminobutan-1-ol dehydrogenase, 4-aminobutan-1-ol oxidoreductase (deaminating) and 4-aminobutan-1-ol transaminase;   (q) 4-aminobutyrate kinase, 4-aminobutyraldehyde dehydrogenase (phosphorylating), 4-aminobutan-1-ol dehydrogenase, 4-aminobutan-1-ol oxidoreductase (deaminating), 4-aminobutan-1-ol transaminase, [(4-aminobutanolyl)oxy]phosphonic acid oxidoreductase (deaminating), [(4-aminobutanolyl)oxy]phosphonic acid transaminase, 4-hydroxybutyryl-phosphate dehydrogenase, and 4-hydroxybutyraldehyde dehydrogenase (phosphorylating);   (r) alpha-ketoglutarate 5-kinase, 2,5-dioxopentanoic semialdehyde dehydrogenase (phosphorylating), 2,5-dioxopentanoic acid reductase, alpha-ketoglutarate CoA transferase, alpha-ketoglutaryl-CoA hydrolase, alpha-ketoglutaryl-CoA ligase, alpha-ketoglutaryl-CoA reductase, 5-hydroxy-2-oxopentanoic acid dehydrogenase, alpha-ketoglutaryl-CoA reductase (alcohol forming), 5-hydroxy-2-oxopentanoic acid decarboxylase, and 5-hydroxy-2-oxopentanoic acid dehydrogenase (decarboxylation);   (s) glutamate CoA transferase, glutamyl-CoA hydrolase, glutamyl-CoA ligase, glutamate 5-kinase, glutamate-5-semialdehyde dehydrogenase (phosphorylating), glutamyl-CoA reductase, glutamate-5-semialdehyde reductase, glutamyl-CoA reductase (alcohol forming), 2-amino-5-hydroxypentanoic acid oxidoreductase (deaminating), 2-amino-5-hydroxypentanoic acid transaminase, 5-hydroxy-2-oxopentanoic acid decarboxylase, 5-hydroxy-2-oxopentanoic acid dehydrogenase (decarboxylation);   (t) 3-hydroxybutyryl-CoA dehydrogenase, 3-hydroxybutyryl-CoA dehydratase, vinylacetyl-CoA Δ-isomerase, or 4-hydroxybutyryl-CoA dehydratase;   (u) homoserine deaminase, homoserine CoA transferase, homoserine-CoA hydrolase, homoserine-CoA ligase, homoserine-CoA deaminase, 4-hydroxybut-2-enoyl-CoA transferase, 4-hydroxybut-2-enoyl-CoA hydrolase, 4-hydroxybut-2-enoyl-CoA ligase, 4-hydroxybut-2-enoate reductase, 4-hydroxybutyryl-CoA transferase, 4-hydroxybutyryl-CoA hydrolase, 4-hydroxybutyryl-CoA ligase, or 4-hydroxybut-2-enoyl-CoA reductase;   (v) succinyl-CoA reductase (alcohol forming), 4-hydroxybutyryl-CoA hydrolase, 4-hydroxybutyryl-CoA ligase, or 4-hydroxybutanal dehydrogenase (phosphorylating);   (w) glutamate dehydrogenase, 4-aminobutyrate oxidoreductase (deaminating), 4-aminobutyrate transaminase, glutamate decarboxylase, 4-hydroxybutyryl-CoA hydrolase, 4-hydroxybutyryl-CoA ligase, or 4-hydroxybutanal dehydrogenase (phosphorylating);   (x) 4-aminobutyrate kinase; 4-aminobutyraldehyde dehydrogenase (phosphorylating); 4-aminobutan-1-ol dehydrogenase; and 4-aminobutan-1-ol oxidoreductase (deaminating) or 4-aminobutan-1-ol transaminase;   (y) 4-aminobutyrate kinase; [(4-aminobutanolyl)oxy]phosphonic acid oxidoreductase (deaminating) or [(4-aminobutanolyl)oxy]phosphonic acid transaminase; 4-hydroxybutyryl-phosphate dehydrogenase; and 4-hydroxybutyraldehyde dehydrogenase (phosphorylating);   (z) alpha-ketoglutarate CoA transferase, alpha-ketoglutaryl-CoA hydrolase, or alpha-ketoglutaryl-CoA ligase; alpha-ketoglutaryl-CoA reductase (alcohol forming); and 5-hydroxy-2-oxopentanoic acid decarboxylase;   (aa) alpha-ketoglutarate CoA transferase, alpha-ketoglutaryl-CoA hydrolase, or alpha-ketoglutaryl-CoA ligase; alpha-ketoglutaryl-CoA reductase (alcohol forming); and 5-hydroxy-2-oxopentanoic acid dehydrogenase (decarboxylation);   (bb) alpha-ketoglutarate 5-kinase; 2,5-dioxopentanoic semialdehyde dehydrogenase (phosphorylating); 2,5-dioxopentanoic acid reductase; and 5-hydroxy-2-oxopentanoic acid decarboxylase;   (cc) alpha-ketoglutarate 5-kinase; 2,5-dioxopentanoic semialdehyde dehydrogenase (phosphorylating); 2,5-dioxopentanoic acid reductase; and 5-hydroxy-2-oxopentanoic acid dehydrogenase (decarboxylation);   (dd) alpha-ketoglutarate CoA transferase, alpha-ketoglutaryl-CoA hydrolase, or alpha-ketoglutaryl-CoA ligase; alpha-ketoglutaryl-CoA reductase; 5-hydroxy-2-oxopentanoic acid dehydrogenase; and 5-hydroxy-2-oxopentanoic acid decarboxylase;   (ee) alpha-ketoglutarate CoA transferase, alpha-ketoglutaryl-CoA hydrolase, or alpha-ketoglutaryl-CoA ligase; alpha-ketoglutaryl-CoA reductase; 5-hydroxy-2-oxopentanoic acid dehydrogenase; and 5-hydroxy-2-oxopentanoic acid dehydrogenase (decarboxylation);   (ff) glutamate CoA transferase, glutamyl-CoA hydrolase, or glutamyl-CoA ligase; glutamyl-CoA reductase (alcohol forming); 2-amino-5-hydroxypentanoic acid oxidoreductase (deaminating) or 2-amino-5-hydroxypentanoic acid transaminase; and 5-hydroxy-2-oxopentanoic acid decarboxylase or 5-hydroxy-2-oxopentanoic acid dehydrogenase (decarboxylation);   (gg) glutamate 5-kinase; glutamate-5-semialdehyde dehydrogenase (phosphorylating); 2-amino-5-hydroxypentanoic acid oxidoreductase (deaminating) or 2-amino-5-hydroxypentanoic acid transaminase; and 5-hydroxy-2-oxopentanoic acid decarboxylase or 5-hydroxy-2-oxopentanoic acid dehydrogenase (decarboxylation);   (hh) glutamate CoA transferase, glutamyl-CoA hydrolase, or glutamyl-CoA ligase; glutamyl-CoA reductase; glutamate-5-semialdehyde reductase; 2-amino-5-hydroxypentanoic acid oxidoreductase (deaminating) or 2-amino-5-hydroxypentanoic acid transaminase; and 5-hydroxy-2-oxopentanoic acid decarboxylase or 5-hydroxy-2-oxopentanoic acid dehydrogenase (decarboxylation);   (ii) glutamate 5-kinase; glutamate-5-semialdehyde dehydrogenase (phosphorylating); glutamate-5-semialdehyde reductase; 2-amino-5-hydroxypentanoic acid oxidoreductase (deaminating) or 2-amino-5-hydroxypentanoic acid transaminase; and 5-hydroxy-2-oxopentanoic acid decarboxylase or 5-hydroxy-2-oxopentanoic acid dehydrogenase (decarboxylation);   (jj) homoserine deaminase; 4-hydroxybut-2-enoyl-CoA transferase, 4-hydroxybut-2-enoyl-CoA hydrolase, 4-hydroxybut-2-enoyl-CoA ligase; 4-hydroxybut-2-enoyl-CoA reductase;   (kk) homoserine CoA transferase, homoserine-CoA hydrolase, or homoserine-CoA ligase; homoserine-CoA deaminase; and 4-hydroxybut-2-enoyl-CoA reductase;   (ll) homoserine deaminase; 4-hydroxybut-2-enoate reductase; and 4-hydroxybutyryl-CoA transferase, 4-hydroxybutyryl-CoA hydrolase, or 4-hydroxybutyryl-CoA ligase;   (mm) (i) alpha-ketoglutarate decarboxylase; or alpha-ketoglutarate dehydrogenase and CoA-dependent succinate semialdehyde dehydrogenase; or glutamate:succinate semialdehyde transaminase and glutamate decarboxylase; (ii) 4-hydroxybutyrate dehydrogenase; (iii) 4-hydroxybutyryl-CoA transferase; or 4-hydroxybutyrate kinase and phosphotrans-4-hydroxybutyrylase; and (iv) 4-hydroxybutyryl-CoA reductase;   (nn) (i) alpha-ketoglutarate decarboxylase; or succinyl-CoA synthetase and CoA-dependent succinate semialdehyde dehydrogenase; (ii) 4-hydroxybutyrate dehydrogenase; (iii) 4-hydroxybutyryl-CoA transferase; or 4-hydroxybutyrate kinase and phosphotrans-4-hydroxybutyrylase;   (oo) (i) alpha-ketoglutarate decarboxylase; or glutamate dehydrogenase; glutamate decarboxylase; and deaminating 4-aminobutyrate oxidoreductase or 4-aminobutyrate transaminase; or alpha-ketoglutarate dehydrogenase and CoA-dependent succinate semialdehyde dehydrogenase; (ii) 4-hydroxybutyrate dehydrogenase; and (iii) 4-hydroxybutyrate kinase; phosphotrans-4-hydroxybutyrylase; 4-hydroxybutyryl-CoA reductase; and 4-hydroxybutyraldehyde reductase; or 4-hydroxybutyrate kinase; phosphorylating 4-hydroxybutanal dehydrogenase; and 4-hydroxybutyraldehyde reductase; or 4-hydroxybutyrate kinase; phosphotrans-4-hydroxybutyrylase; and alcohol forming 4-hydroxybutyryl-CoA reductase; or 4-hydroxybutyryl-CoA transferase or 4-hydroxybutyryl-CoA hydrolase or 4-hydroxybutyryl-CoA ligase; 4-hydroxybutyryl-CoA reductase; and 4-hydroxybutyraldehyde reductase; or 4-hydroxybutyryl-CoA transferase or 4-hydroxybutyryl-CoA hydrolase or 4-hydroxybutyryl-CoA ligase; and alcohol forming 4-hydroxybutyryl-CoA reductase;   (pp) (i) glutamate CoA transferase or glutamyl-CoA hydrolase or glutamyl-CoA ligase; glutamyl-CoA reductase; and glutamate-5-semialdehyde reductase; or glutamate CoA transferase or glutamyl-CoA hydrolase or glutamyl-CoA ligase; and alcohol forming glutamyl-CoA reductase; or glutamate 5-kinase; phosphorylating glutamate-5-semialdehyde dehydrogenase; and glutamate-5-semialdehyde reductase; (ii) deaminating 2-amino-5-hydroxypentanoic acid oxidoreductase or 2-amino-5-hydroxypentanoic acid transaminase; and (iii) 5-hydroxy-2-oxopentanoic acid decarboxylase; and 4-hydroxybutyraldehyde reductase; or decarboxylating 5-hydroxy-2-oxopentanoic acid dehydrogenase; 4-hydroxybutyryl-CoA reductase; and 4-hydroxybutyraldehyde reductase; or decarboxylating 5-hydroxy-2-oxopentanoic acid dehydrogenase and alcohol forming 4-hydroxybutyryl-CoA reductase;   (qq) a gamma-butyrolactone pathway comprising a pathway selected from any of the pathways that produce 4-hydroxybutyryl-CoA or 4-hydroxybutyryl phosphate as shown in  FIG. 1 ,  8 - 13 ,  58 ,  62 - 63  or  72 - 74 , wherein gamma-butyrolactone is produced enzymatically or by spontaneous chemical conversion.   
     
     
         23 . The non-naturally occurring microbial organism of  claim 22 , wherein said microbial organism comprising (i) further comprises an exogenous nucleic acid encoding an enzyme selected from a pyruvate:ferredoxin oxidoreductase, an aconitase, a succinyl-CoA synthetase, a succinyl-CoA transferase, a fumarase, a malate dehydrogenase, an acetate kinase, a phosphotransacetylase, an acetyl-CoA synthetase, an NAD(P)H:ferredoxin oxidoreductase, ferredoxin, and combinations thereof. 
     
     
         24 . The non-naturally occurring microbial organism of  claim 22 , wherein said microbial organism comprising (ii) further comprises an exogenous nucleic acid encoding an enzyme selected from an aconitase, an isocitrate dehydrogenase, a succinyl-CoA synthetase, a succinyl-CoA transferase, a fumarase, a malate dehydrogenase, NAD(P):ferredoxin oxidoreductase, ferredoxin, and combinations thereof. 
     
     
         25 . The non-naturally occurring microbial organism of  claim 22 , wherein said microbial organism comprising (iii) further comprises an exogenous nucleic acid encoding an enzyme selected from NAD(P):ferredoxin oxidoreductase and ferredoxin. 
     
     
         26 - 31 . (canceled) 
     
     
         32 . A method for producing gamma-butyrolactone, comprising culturing the non-naturally occurring microbial organism of  claim 22  under conditions and for a sufficient period of time to produce gamma-butyrolactone. 
     
     
         33 . A carboxylic acid reductase, comprising an amino acid sequence having an amino acid substitution selected from E16K; Q95L; L100M; A1011T; K823E; T941S; H15Q; D198E; G446C; S392N; F699L; V8831; F467S; T987S; R12H; V295G; V295A; V295S; V295T; V295G; V295V; V295L; V2951; V295M; V295P; V295F; V295Y; V295W; V295D; V295E; V295N; V295Q; V295H; V295K; V295R; M296G; M296A; M296S; M296T; M296C; M296V; M296L; M2961; M296M; M296P; M296F; M296Y; M296W; M296D; M296E; M296N; M296Q; M296H; M296K; M296R; G297G; G297A; G297S; G297T; G297C; G297V; G297L; G2971; G297M; G297P; G297F; G297Y; G297W; G297D; G297E; G297N; G297Q; G297H; G297K; G297R; G391G; G391A; G391S; G391T; G391C; G391V; G391L; G391I; G391M; G391P; G391F; G391Y; G391W; G391D; G391E; G391N; G391Q; G391H; G391K; G391R; G421G; G421A; G421S; G421T; G421C; G421V; G421L; G421I; G421M; G421P; G421F; G421Y; G421W; G421D; G421E; G421N; G421Q; G421H; G421K; G421R; D413G; D413A; D413S; D413T; D413C; D413V; D413L; D413I; D413M; D413P; D413F; D413Y; D413W; D413D; D413E; D413N; D413Q; D413H; D413K; D413R; G414G; G414A; G414S; G414T; G414C; G414V; G414L; G414I; G414M; G414P; G414F; G414Y; G414W; G414D; G414E; G414N; G414Q; G414H; G414K; G414R; Y415G; Y415A; Y415S; Y415T; Y415C; Y415V; Y415L; Y415I; Y415M; Y415P; Y415F; Y415Y; Y415W; Y415D; Y415E; Y415N; Y415Q; Y415H; Y415K; Y415R; G416G; G416A; G416S; G416T; G416C; G416V; G416L; G416I; G416M; G416P; G416F; G416Y; G416W; G416D; G416E; G416N; G416Q; G416H; G416K; G416R; S417G; 5417A; S417S; S417T; S417C; S417V S417L; S417I; S417M; S417P; S417F; S417Y; S417W; S417D; S417E; S417N; S417Q; S417H; S417K; and S417R, or combinations thereof.