Pyruvate dehydrogenase bypass and acetate-dependent acetyl-CoA synthesis

The pyruvate dehydrogenase (PDH) bypass makes acetyl-CoA in the cytosol without the mitochondrial PDH complex. Acetaldehyde is oxidised by an aldehyde dehydrogenase to acetate, and acetate is ligated to coenzyme A by an AMP-forming acetyl-CoA synthetase. The acetaldehyde comes either from pyruvate decarboxylase during growth on sugars or from alcohol dehydrogenase oxidising ethanol during growth on ethanol. Acetyl-CoA cannot cross organelle membranes, and some fungi, including budding yeast, lack ATP-citrate lyase. In those organisms this route is the main or only source of nucleocytosolic acetyl-CoA for fatty acid and sterol synthesis, lysine synthesis and histone acetylation, and it is essential. The same three reactions carry ethanol and acetate into central metabolism (via the glyoxylate cycle) after the diauxic shift. The acetate-activation step is the conserved acetyl-CoA synthetase found from bacteria to mammals.

MODULE:pdh_bypass_acetyl_coa_synthesisDRAFTABSTRACTMetabolic Pathwaymodules/pdh_bypass_acetyl_coa_synthesis.yaml
acetyl-CoA biosynthetic processGO:0006085
GO:0006085
acetyl-CoA biosynthetic process
Module-level process. GO has no more specific term for acetyl-CoA formation from acetaldehyde via acetate. GO:0006086 (pyruvate decarboxylation to acetyl-CoA) denotes the PDH complex route that this module bypasses.
GO:0006068
ethanol catabolic process
Concept for the ethanol-oxidation entry variant (YeastPathways PWY3O-4300).
GO:0019413
acetate biosynthetic process
Concept for the aldehyde dehydrogenase step that forms acetate.
YeastPathways:PWY3O-4300
ethanol degradation
Source for the ethanol entry and the ALD-ACS chain. Corrections: the frame lists ADH1-ADH5 for ethanol oxidation, but ADH2 is the glucose-repressed, ethanol-oxidising isozyme (ADH1 is fermentative), so only ADH2 is used for this direction. The frame gives no gene for the acetaldehyde dehydrogenase reaction (RXN66-3). Its GO-CAM fills that reaction with ALD2 and the acetylating (CoA-dependent) MF GO:0008774, which is wrong on both counts. Ald6 (cytosolic) and Ald4 (mitochondrial) are the enzymes needed for growth on ethanol (PMID:9675847), and the yeast enzymes form free acetate, not acetyl-CoA.
YeastPathways:ACETATEUTIL2-PWY
acetate utilization
Source for the acetate-activation step (ACS1, ACS2); accepted unchanged.
YeastPathways:GLUCFERMEN-PWY
superpathway of glucose fermentation
Supplies the sugar-growth arm: PDC1/PDC5/PDC6 make acetaldehyde, and ALD6 (NADP+, cytosol) and ALD4/ALD5 (mitochondria) oxidise it. The ALD2 and ALD3 assignments in the frame are not supported as bypass members (PMID:15256563).
PMID:7649171
ACS2, a Saccharomyces cerevisiae gene encoding acetyl-coenzyme A synthetase, essential for growth on glucose.
Defines the PDH bypass and shows that ACS2 is essential on glucose and the acs1 acs2 double mutant is inviable.
indirectly via the so-called PDH bypass, which requires the sequential action of pyruvate decarboxylase, acetaldehyde dehydrogenase and acetyl-coenzyme A synthetase.
PMID:8910545
The two acetyl-coenzyme A synthetases of Saccharomyces cerevisiae differ with respect to kinetic properties and transcriptional regulation.
Acs1 is the high-affinity, glucose-repressed "aerobic" form and Acs2 the constitutive "non-aerobic" form.
The Km for acetate of Acs1p was about 30-fold lower than that of Acs2p
PMID:16857587
Nucleocytosolic acetyl-coenzyme a synthetase is required for histone acetylation and global transcription.
Acs2 (and Acs1 on non-fermentable carbon) supplies the nucleocytosolic acetyl-CoA used for histone acetylation.
Yeast mitochondrial and nucleocytosolic acetyl-CoA pools are biochemically isolated.
PMID:22876324
Profiling of cytosolic and peroxisomal acetyl-CoA metabolism in Saccharomyces cerevisiae.
Acetyl-CoA is not transported between compartments, so the cytosolic pool must be made in place.
Membranes separating intracellular compartments are impermeable to acetyl-CoA and no direct transport between the compartments occurs.
PMID:8904337
Pyruvate decarboxylase: an indispensable enzyme for growth of Saccharomyces cerevisiae on glucose.
Pdc-negative yeast cannot grow on glucose without added C2 compounds; mitochondrial PDH cannot supply cytosolic acetyl-CoA.
It is concluded that the mitochondrial pyruvate dehydrogenase complex cannot function as the sole source of acetyl-CoA during growth of S. cerevisiae on glucose
PMID:10234824
Growth requirements of pyruvate-decarboxylase-negative Saccharomyces cerevisiae.
The acetate requirement of Pdc-negative yeast equals the cytosolic acetyl-CoA demand for lipid and lysine synthesis.
consistent with the proposed role of pyruvate decarboxylase in the synthesis of cytosolic acetyl-CoA.
PMID:9392076
The ALD6 gene of Saccharomyces cerevisiae encodes a cytosolic, Mg(2+)-activated acetaldehyde dehydrogenase.
ALD6 encodes the cytosolic Mg2+-activated acetaldehyde dehydrogenase; ald6 mutants grow slowly on glucose and cannot use ethanol.
This enzyme is thought to be involved in the production of acetate from which cytosolic acetyl-CoA is then synthesized.
PMID:9675847
Identification and disruption of the gene encoding the K(+)-activated acetaldehyde dehydrogenase of Saccharomyces cerevisiae.
YOR374w (ALD4/ALD7) encodes the mitochondrial K+-activated acetaldehyde dehydrogenase, required with Ald6 for growth on ethanol.
both the Mg(2+)- and K(+)-ACDHs are required for growth on ethanol, whilst only the former plays a role during growth on glucose.
PMID:15256563
Functional analysis of the ALD gene family of Saccharomyces cerevisiae during anaerobic growth on glucose: the NADP+-dependent Ald6p and Ald5p isoforms play a major role in acetate formation.
Acetate is made mainly by cytosolic Ald6 and mitochondrial Ald5; Ald2 and Ald3 do not contribute.
Thus, acetate is mainly produced by the cytosolic PDH bypass via Ald6p and by a mitochondrial route involving Ald5p.
PMID:10919763
Engineering of the pyruvate dehydrogenase bypass in Saccharomyces cerevisiae: role of the cytosolic Mg(2+) and mitochondrial K(+) acetaldehyde dehydrogenases Ald6p and Ald4p in acetate formation during alcoholic fermentation.
Ald4 can partially replace Ald6.
a strain lacking both Ald6p and Ald4p exhibited a long delay in growth and acetate production, suggesting that Ald4p can partially replace the Ald6p isoform.
PMID:11589696
Participation of acetaldehyde dehydrogenases in ethanol and pyruvate metabolism of the yeast Saccharomyces cerevisiae.
The relative contribution of mitochondrial Ald4 and cytosolic Ald6 on ethanol depends on strain background.
when cultured on ethanol, the cytosolic acetaldehyde dehydrogenase can partially compensate for the lack of mitochondrial acetaldehyde dehydrogenase only when the activity of the cytosolic enzyme is sufficient.
PMID:15864308
Resurrecting ancestral alcohol dehydrogenases from yeast.
Adh2 is the paralog that consumes the accumulated ethanol.
Yeast later consumes the accumulated ethanol, exploiting Adh2, an Adh1 homolog differing by 24 (of 348) amino acids.
PMID:11495982
Adr1 and Cat8 synergistically activate the glucose-regulated alcohol dehydrogenase gene ADH2 of the yeast Saccharomyces cerevisiae.
ADH2 is glucose-repressed and activated by Adr1 and Cat8.
Glucose-repressible alcohol dehydrogenase II, encoded by the ADH2 gene of the yeast Saccharomyces cerevisiae, is transcriptionally controlled by the activator Adr1
8Nodes
3Parts
2Variant Sets
4Variants
6Annotons
2Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

No MODULE:pdh_bypass_acetyl_coa_synthesis deep-research report alongside the module YAML.

Leaf nodes lacking representative members

✓ representative grounding skipped for abstract module.

Template conformance

✓ every declared conforms_to bundle matches its template motif.

Function consistency and core coverage

8 gene-function check(s) reflected in core functions · 0 conflict(s) · 6 evidence or coverage gap(s) (28 comparison(s))

Retained noncore functions are reported separately; they do not require promotion to core functions. Support from representative genes does not establish conservation across the whole family. Missing reviews or identifiers leave a claim unverified.

AnnotonParticipantFunctionAssessment
bypass_pdc_activity PDC1 (S. cerevisiae)
UniProtKB:P06169
Family Representative 		pyruvate decarboxylase activity
GO:0004737 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
bypass_pdc_activity PDC5 (S. cerevisiae)
UniProtKB:P16467
Family Representative 		pyruvate decarboxylase activity
GO:0004737 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
bypass_pdc_activity PDC6 (S. cerevisiae)
UniProtKB:P26263
Family Representative 		pyruvate decarboxylase activity
GO:0004737 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
ethanol_oxidising_adh_activity ADH2 (S. cerevisiae)
UniProtKB:P00331
Family Representative 		ethanol dehydrogenase (NAD+) activity
GO:0120542 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
cytosolic_aldh_activity ALD6 (S. cerevisiae)
UniProtKB:P54115
Family Representative 		acetaldehyde dehydrogenase (NADP+) activity
GO:0140088 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
mitochondrial_aldh_nad_activity ALD4 (S. cerevisiae)
UniProtKB:P46367
Family Representative 		acetaldehyde dehydrogenase (NAD+) activity
GO:0140087 		Function Unreviewed
No retained annotation or core molecular function supports this GO assertion. Missing or broader evidence is a coverage gap, not proof the activity is absent.
mitochondrial_aldh_nadp_activity ALD5 (S. cerevisiae)
UniProtKB:P40047
Family Representative 		acetaldehyde dehydrogenase (NADP+) activity
GO:0140088 		Annotation Supported
A retained annotation or curated replacement supports this function, but core_functions does not yet reflect it.
acs_activity ACS2 (S. cerevisiae)
UniProtKB:P52910
Family Representative 		acetyl-CoA synthetase activity
GO:0003987 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
acs_activity ACS1 (S. cerevisiae)
UniProtKB:Q01574
Family Representative 		acetyl-CoA synthetase activity
GO:0003987 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
acs_activity ACSS2 (human)
UniProtKB:Q9NR19
Family Representative 		acetyl-CoA synthetase activity
GO:0003987 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
acs_activity acs (Escherichia coli K-12)
UniProtKB:P27550
Family Representative 		acetyl-CoA synthetase activity
GO:0003987 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
bypass_pdc_activity thiamine-diphosphate-dependent pyruvate decarboxylase
PANTHER:PTHR43452:SF30
Family 		pyruvate decarboxylase activity
GO:0004737 		Family Supported
Family review supports GO:0004737 for PANTHER:PTHR43452:SF30. Safe for the canonical PDC subfamilies, which include the yeast PDC1/PDC5/PDC6 (SF30), the Zymomonas/Neurospora/fission-yeast pdc101/pdc102 group (SF1), fission yeast pdc201 (SF36) and the plant PDC subfamilies. Not safe for SF3 (ARO10, experimentally lacking pyruvate activity). Within SF30, THI3 is an exception, and the bacterial IpdC/Kdc members of SF30 were not assessed here and should not be assumed to be pyruvate decarboxylases on subfamily grounds. This is the term the alcoholic fermentation and PDH bypass modules require of the family.
bypass_pdc_activity thiamine-diphosphate-dependent pyruvate decarboxylase
PANTHER:PTHR43452:SF1
Family 		pyruvate decarboxylase activity
GO:0004737 		Family Supported
Family review supports GO:0004737 for PANTHER:PTHR43452:SF1. Safe for the canonical PDC subfamilies, which include the yeast PDC1/PDC5/PDC6 (SF30), the Zymomonas/Neurospora/fission-yeast pdc101/pdc102 group (SF1), fission yeast pdc201 (SF36) and the plant PDC subfamilies. Not safe for SF3 (ARO10, experimentally lacking pyruvate activity). Within SF30, THI3 is an exception, and the bacterial IpdC/Kdc members of SF30 were not assessed here and should not be assumed to be pyruvate decarboxylases on subfamily grounds. This is the term the alcoholic fermentation and PDH bypass modules require of the family.
bypass_pdc_activity thiamine-diphosphate-dependent pyruvate decarboxylase
PANTHER:PTHR43452:SF36
Family 		pyruvate decarboxylase activity
GO:0004737 		Family Supported
Family review supports GO:0004737 for PANTHER:PTHR43452:SF36. Safe for the canonical PDC subfamilies, which include the yeast PDC1/PDC5/PDC6 (SF30), the Zymomonas/Neurospora/fission-yeast pdc101/pdc102 group (SF1), fission yeast pdc201 (SF36) and the plant PDC subfamilies. Not safe for SF3 (ARO10, experimentally lacking pyruvate activity). Within SF30, THI3 is an exception, and the bacterial IpdC/Kdc members of SF30 were not assessed here and should not be assumed to be pyruvate decarboxylases on subfamily grounds. This is the term the alcoholic fermentation and PDH bypass modules require of the family.
bypass_pdc_activity thiamine-diphosphate-dependent pyruvate decarboxylase
PANTHER:PTHR43452:SF11
Family 		pyruvate decarboxylase activity
GO:0004737 		Family Supported
Family review supports GO:0004737 for PANTHER:PTHR43452:SF11. Safe for the canonical PDC subfamilies, which include the yeast PDC1/PDC5/PDC6 (SF30), the Zymomonas/Neurospora/fission-yeast pdc101/pdc102 group (SF1), fission yeast pdc201 (SF36) and the plant PDC subfamilies. Not safe for SF3 (ARO10, experimentally lacking pyruvate activity). Within SF30, THI3 is an exception, and the bacterial IpdC/Kdc members of SF30 were not assessed here and should not be assumed to be pyruvate decarboxylases on subfamily grounds. This is the term the alcoholic fermentation and PDH bypass modules require of the family.
bypass_pdc_activity thiamine-diphosphate-dependent pyruvate decarboxylase
PANTHER:PTHR43452:SF18
Family 		pyruvate decarboxylase activity
GO:0004737 		Family Supported
Family review supports GO:0004737 for PANTHER:PTHR43452:SF18. Safe for the canonical PDC subfamilies, which include the yeast PDC1/PDC5/PDC6 (SF30), the Zymomonas/Neurospora/fission-yeast pdc101/pdc102 group (SF1), fission yeast pdc201 (SF36) and the plant PDC subfamilies. Not safe for SF3 (ARO10, experimentally lacking pyruvate activity). Within SF30, THI3 is an exception, and the bacterial IpdC/Kdc members of SF30 were not assessed here and should not be assumed to be pyruvate decarboxylases on subfamily grounds. This is the term the alcoholic fermentation and PDH bypass modules require of the family.
bypass_pdc_activity thiamine-diphosphate-dependent pyruvate decarboxylase
PANTHER:PTHR43452:SF7
Family 		pyruvate decarboxylase activity
GO:0004737 		Family Supported
Family review supports GO:0004737 for PANTHER:PTHR43452:SF7. Safe for the canonical PDC subfamilies, which include the yeast PDC1/PDC5/PDC6 (SF30), the Zymomonas/Neurospora/fission-yeast pdc101/pdc102 group (SF1), fission yeast pdc201 (SF36) and the plant PDC subfamilies. Not safe for SF3 (ARO10, experimentally lacking pyruvate activity). Within SF30, THI3 is an exception, and the bacterial IpdC/Kdc members of SF30 were not assessed here and should not be assumed to be pyruvate decarboxylases on subfamily grounds. This is the term the alcoholic fermentation and PDH bypass modules require of the family.
bypass_pdc_activity thiamine-diphosphate-dependent pyruvate decarboxylase
PANTHER:PTHR43452:SF6
Family 		pyruvate decarboxylase activity
GO:0004737 		Family Supported
Family review supports GO:0004737 for PANTHER:PTHR43452:SF6. Safe for the canonical PDC subfamilies, which include the yeast PDC1/PDC5/PDC6 (SF30), the Zymomonas/Neurospora/fission-yeast pdc101/pdc102 group (SF1), fission yeast pdc201 (SF36) and the plant PDC subfamilies. Not safe for SF3 (ARO10, experimentally lacking pyruvate activity). Within SF30, THI3 is an exception, and the bacterial IpdC/Kdc members of SF30 were not assessed here and should not be assumed to be pyruvate decarboxylases on subfamily grounds. This is the term the alcoholic fermentation and PDH bypass modules require of the family.
bypass_pdc_activity thiamine-diphosphate-dependent pyruvate decarboxylase
PANTHER:PTHR43452:SF20
Family 		pyruvate decarboxylase activity
GO:0004737 		Family Supported
Family review supports GO:0004737 for PANTHER:PTHR43452:SF20. Safe for the canonical PDC subfamilies, which include the yeast PDC1/PDC5/PDC6 (SF30), the Zymomonas/Neurospora/fission-yeast pdc101/pdc102 group (SF1), fission yeast pdc201 (SF36) and the plant PDC subfamilies. Not safe for SF3 (ARO10, experimentally lacking pyruvate activity). Within SF30, THI3 is an exception, and the bacterial IpdC/Kdc members of SF30 were not assessed here and should not be assumed to be pyruvate decarboxylases on subfamily grounds. This is the term the alcoholic fermentation and PDH bypass modules require of the family.
bypass_pdc_activity thiamine-diphosphate-dependent pyruvate decarboxylase
PANTHER:PTHR43452:SF39
Family 		pyruvate decarboxylase activity
GO:0004737 		Family Supported
Family review supports GO:0004737 for PANTHER:PTHR43452:SF39. Safe for the canonical PDC subfamilies, which include the yeast PDC1/PDC5/PDC6 (SF30), the Zymomonas/Neurospora/fission-yeast pdc101/pdc102 group (SF1), fission yeast pdc201 (SF36) and the plant PDC subfamilies. Not safe for SF3 (ARO10, experimentally lacking pyruvate activity). Within SF30, THI3 is an exception, and the bacterial IpdC/Kdc members of SF30 were not assessed here and should not be assumed to be pyruvate decarboxylases on subfamily grounds. This is the term the alcoholic fermentation and PDH bypass modules require of the family.
bypass_pdc_activity thiamine-diphosphate-dependent pyruvate decarboxylase
PANTHER:PTHR43452:SF5
Family 		pyruvate decarboxylase activity
GO:0004737 		Family Supported
Family review supports GO:0004737 for PANTHER:PTHR43452:SF5. Safe for the canonical PDC subfamilies, which include the yeast PDC1/PDC5/PDC6 (SF30), the Zymomonas/Neurospora/fission-yeast pdc101/pdc102 group (SF1), fission yeast pdc201 (SF36) and the plant PDC subfamilies. Not safe for SF3 (ARO10, experimentally lacking pyruvate activity). Within SF30, THI3 is an exception, and the bacterial IpdC/Kdc members of SF30 were not assessed here and should not be assumed to be pyruvate decarboxylases on subfamily grounds. This is the term the alcoholic fermentation and PDH bypass modules require of the family.
bypass_pdc_activity thiamine-diphosphate-dependent pyruvate decarboxylase
PANTHER:PTHR43452:SF38
Family 		pyruvate decarboxylase activity
GO:0004737 		Family Supported
Family review supports GO:0004737 for PANTHER:PTHR43452:SF38. Safe for the canonical PDC subfamilies, which include the yeast PDC1/PDC5/PDC6 (SF30), the Zymomonas/Neurospora/fission-yeast pdc101/pdc102 group (SF1), fission yeast pdc201 (SF36) and the plant PDC subfamilies. Not safe for SF3 (ARO10, experimentally lacking pyruvate activity). Within SF30, THI3 is an exception, and the bacterial IpdC/Kdc members of SF30 were not assessed here and should not be assumed to be pyruvate decarboxylases on subfamily grounds. This is the term the alcoholic fermentation and PDH bypass modules require of the family.
ethanol_oxidising_adh_activity zinc-containing medium-chain alcohol dehydrogenase
PANTHER:PTHR42940:SF3
Family 		ethanol dehydrogenase (NAD+) activity
GO:0120542 		Family Supported
Family review supports GO:0120542 for PANTHER:PTHR42940:SF3. The term both modules require of this family. Established for the fungal ADH1 group (SF3: ADH1 fermentative direction, ADH2 oxidative direction, ADH3 mitochondrial, fission yeast adh1) and plausible for SF5 alcB, a PAINT seed for the fungal ADH node. Not safe for SF7 (secondary-metabolism dehydrogenases) or SF8 as a whole (contains CoA-thioester reductases). ADH5 is an active but minor isozyme and is annotated only to the parent alcohol dehydrogenase activity in its review.
ethanol_oxidising_adh_activity zinc-containing medium-chain alcohol dehydrogenase
PANTHER:PTHR42940:SF5
Family 		ethanol dehydrogenase (NAD+) activity
GO:0120542 		Family Supported
Family review supports GO:0120542 for PANTHER:PTHR42940:SF5. The term both modules require of this family. Established for the fungal ADH1 group (SF3: ADH1 fermentative direction, ADH2 oxidative direction, ADH3 mitochondrial, fission yeast adh1) and plausible for SF5 alcB, a PAINT seed for the fungal ADH node. Not safe for SF7 (secondary-metabolism dehydrogenases) or SF8 as a whole (contains CoA-thioester reductases). ADH5 is an active but minor isozyme and is annotated only to the parent alcohol dehydrogenase activity in its review.
cytosolic_aldh_activity aldehyde dehydrogenase family
PANTHER:PTHR11699
Family 		acetaldehyde dehydrogenase (NADP+) activity
GO:0140088 		Family Function Unreviewed
Family review leaves GO:0140088 UNRESOLVED. Sound for the yeast PDH-bypass aldehyde dehydrogenases -- cytosolic ALD6 (essentially NADP+-specific) and mitochondrial ALD4 and ALD5, whose gene reviews accept GO:0140088 on EXP evidence -- but not expressible with the available subfamily axis. The PANTHER 19.0 member index places ALD6 (P54115) and ALD4 (P46367) in SF268 and ALD5 (P40047) in SF211; UniProt gives these entries no subfamily. SF268 holds only those two yeast enzymes among the reference genomes, but SF211 is heterogeneous: besides ALD5 it holds the vertebrate ALDH16A1 orthologs (human ALDH16A1 has lost the catalytic cysteine and glutamate) and bacterial aldehyde dehydrogenases that act on other aldehydes, such as E. coli PatD and FeaB. Scoping the term to SF211 would assert acetaldehyde NADP+ dehydrogenase activity for all of them, so pdh_bypass_acetyl_coa_synthesis selects these steps at family level with the yeast enzymes as representative members.
mitochondrial_aldh_nad_activity aldehyde dehydrogenase family
PANTHER:PTHR11699
Family 		acetaldehyde dehydrogenase (NAD+) activity
GO:0140087 		Family Function Unreviewed
Family review leaves GO:0004029 UNRESOLVED. Sound where PAINT scopes it (the PTN000192666 clade minus the ALDH1L branch flagged for pruning), but not safe family-wide and not expressible with the available scoping axes. Not FAMILY_WIDE: the family also holds NADP(+)-preferring members -- the ALDH1L/FDH clade (SF120, SF131), whose intact ALDH domain is strictly NADP+-dependent and whose in-repo rat Aldh1l1 gene review MODIFYs this exact term to GO:0033721, and the subfamily officially named "SUCCINATE-SEMIALDEHYDE DEHYDROGENASE [NADP(+)] 2-RELATED" -- plus CoA-acylating EutE-type enzymes whose chemistry the term does not describe, and the degenerate ALDH16A1. Not RESIDUE_DETERMINED: retention of the catalytic cysteine is necessary but does not determine NAD+ versus NADP+ cofactor specificity, so a residue site alone would over-grant the NAD+-specific term. Not SUBFAMILY_ONLY: the family has ~47 subfamilies, many genuinely NAD+-dependent (ALDH2, ALDH1A1, ALDH1B1, ALDH9A1, yeast and bacterial members), and enumerating every safe subfamily is beyond this review's scope. The practical guidance is per-node, as PAINT already does it: inherit from PTN000192666 (with the ALDH1L branch pruned), and treat as a non-core generic parent for substrate-specialized members such as the ALDH1A branch.
mitochondrial_aldh_nadp_activity aldehyde dehydrogenase family
PANTHER:PTHR11699
Family 		acetaldehyde dehydrogenase (NADP+) activity
GO:0140088 		Family Function Unreviewed
Family review leaves GO:0140088 UNRESOLVED. Sound for the yeast PDH-bypass aldehyde dehydrogenases -- cytosolic ALD6 (essentially NADP+-specific) and mitochondrial ALD4 and ALD5, whose gene reviews accept GO:0140088 on EXP evidence -- but not expressible with the available subfamily axis. The PANTHER 19.0 member index places ALD6 (P54115) and ALD4 (P46367) in SF268 and ALD5 (P40047) in SF211; UniProt gives these entries no subfamily. SF268 holds only those two yeast enzymes among the reference genomes, but SF211 is heterogeneous: besides ALD5 it holds the vertebrate ALDH16A1 orthologs (human ALDH16A1 has lost the catalytic cysteine and glutamate) and bacterial aldehyde dehydrogenases that act on other aldehydes, such as E. coli PatD and FeaB. Scoping the term to SF211 would assert acetaldehyde NADP+ dehydrogenase activity for all of them, so pdh_bypass_acetyl_coa_synthesis selects these steps at family level with the yeast enzymes as representative members.
acs_activity AMP-forming acetyl-CoA synthetase
PANTHER:PTHR24095
Family 		acetyl-CoA synthetase activity
GO:0003987 		Family Supported
Family review supports GO:0003987 FAMILY_WIDE. Asserted by pdh_bypass_acetyl_coa_synthesis and fatty_acid_de_novo_synthesis; accepted by ACS1, ACS2 and both P. putida AcsA paralogs.

Gene-review completeness (10/11 grounded genes reviewed)

6 complete review(s) · 9 with deep research · 1 missing review · 1 reviewed but lacking deep research

Gene Review Complete Deep research
acs P27550 ✓ ✓ ✗
ACS1 Q01574 ✓ ✓ ✓
ACS2 P52910 ✓ 26/27 ✓
ADH2 P00331 ✓ ✓ ✓
ALD4 P46367 ✓ ✓ ✓
ALD5 P40047 ✓ ✓ ✓
ALD6 P54115 ✓ ✓ ✓
PDC1 P06169 ✓ 54/59 ✓
PDC5 P16467 ✓ 58/60 ✓
PDC6 P26263 ✓ 47/52 ✓
ACSS2 (human) Q9NR19 ✗ — —

Details

Context
cytosolGO:0005829
PDH bypass / acetate-dependent acetyl-CoA synthesisMetabolic Pathwaypdh_bypass_acetyl_coa_synthesis

(pyruvate -> acetaldehyde + CO2 | ethanol + NAD+ -> acetaldehyde + NADH) -> acetate (NAD(P)H) -> acetyl-CoA (ATP -> AMP + PPi).

acetyl-CoA biosynthetic processGO:0006085
Context
cytosolGO:0005829

Boundary. The module covers acetaldehyde formation (from pyruvate or ethanol), its oxidation to acetate, and acetate activation. The mitochondrial PDH complex (modules/pyruvate_metabolism.yaml), ATP-citrate lyase (animals, plants, oleaginous yeasts; absent from budding yeast), the bacterial acetate kinase / phosphotransacetylase route and the carnitine shuttle are other acetyl-CoA routes, outside this module. Alcoholic fermentation (modules/alcoholic_fermentation.yaml) shares the pyruvate decarboxylase step but reduces, rather than oxidises, the acetaldehyde. YeastCyc corrections. (1) PWY3O-4300 lists ADH1-ADH5 for ethanol oxidation; only ADH2 is the ethanol-oxidising isozyme. ADH1 is fermentative and ADH3 is a mitochondrial shuttle enzyme. (2) The PWY3O-4300 acetaldehyde dehydrogenase reaction (RXN66-3) has no gene in the frame. The GO-CAM assigns it to ALD2 with GO:0008774 acetaldehyde dehydrogenase (acetylating, NAD+) activity. That is wrong: yeast ALDs are non-acylating, ALD2/ALD3 are stress-induced enzymes with no role in acetate formation (PMID:15256563), and Ald6 plus Ald4 are needed for growth on ethanol (PMID:9675847). (3) In GLUCFERMEN-PWY and its GO-CAM, ALD4 and ALD5 are placed in the cytosol, but both are mitochondrial isozymes. Not grounded in fission yeast. No PomBase GO-CAM is linked to this group. The PomBase fermentation model types atd1 (SPAC9E9.09c) as acetaldehyde dehydrogenase (NAD+) in pyruvate fermentation to acetate; it is a candidate fission-yeast member, but its compartment and role in acetyl-CoA supply were not checked here.

Connections

Part 1: acetaldehyde supply
Pyruvate or ethanol to acetaldehydeMetabolic Pathwayacetaldehyde_supply
Variant set: Acetaldehyde sources by carbon source (One Or More)
Pyruvate decarboxylation (growth on sugars)Reactionpyruvate_decarboxylation_variant

Annotons

Pyruvate decarboxylase
bypass_pdc_activity
Participant: Family: thiamine-diphosphate-dependent pyruvate decarboxylase
Family:
thiamine-diphosphate-dependent pyruvate decarboxylase
Representative Members: PDC1 (S. cerevisiae)UniProtKB:P06169 PDC5 (S. cerevisiae)UniProtKB:P16467 PDC6 (S. cerevisiae)UniProtKB:P26263
Required Function:
pyruvate decarboxylase activityGO:0004737

Function

pyruvate decarboxylase activityGO:0004737
Substrates: pyruvate
Products: acetaldehyde CO2

Locations

cytosolGO:0005829

Shared with alcoholic fermentation (modules/alcoholic_fermentation.yaml). Pdc-negative yeast needs C2 supplements on glucose (PMID:8904337, PMID:10234824).

Ethanol oxidation (growth on ethanol)Reactionethanol_oxidation_variant
ethanol catabolic processGO:0006068

Annotons

Ethanol-oxidising alcohol dehydrogenase
ethanol_oxidising_adh_activity
Participant: Family: zinc-containing medium-chain alcohol dehydrogenase
Family:
zinc-containing medium-chain alcohol dehydrogenase
Representative Members: ADH2 (S. cerevisiae)UniProtKB:P00331
Required Function:
ethanol dehydrogenase (NAD+) activityGO:0120542

Function

ethanol dehydrogenase (NAD+) activityGO:0120542
Substrates: ethanol NAD(+)
Products: acetaldehyde NADH

Locations

cytosolGO:0005829

The reverse of the fermentative ADH step, done by a paralog with a lower Km for ethanol.

Part 2: acetaldehyde oxidation to acetate
Acetaldehyde + NAD(P)+ to acetate + NAD(P)HReactionacetaldehyde_dehydrogenase_step

Non-acylating aldehyde dehydrogenases make free acetate. In fungi the cytosolic NADP+-dependent enzyme is the main supplier and also a source of cytosolic NADPH. Mitochondrial isozymes contribute, and their acetate diffuses to the cytosol.

acetate biosynthetic processGO:0019413
Variant set: Aldehyde dehydrogenase compartment by compartment (One Or More)
Cytosolic NADP+-dependent acetaldehyde dehydrogenaseReactioncytosolic_aldh_variant

Annotons

Cytosolic acetaldehyde dehydrogenase (NADP+)
cytosolic_aldh_activity
Participant: Family: aldehyde dehydrogenase family
Family:
aldehyde dehydrogenase familyPANTHER:PTHR11699
Representative Members: ALD6 (S. cerevisiae)UniProtKB:P54115
Required Function:
acetaldehyde dehydrogenase (NADP+) activityGO:0140088

Function

acetaldehyde dehydrogenase (NADP+) activityGO:0140088
Substrates: acetaldehyde NADP(+) H2O
Products: acetate NADPH

Locations

cytosolGO:0005829
Mitochondrial acetaldehyde dehydrogenasesReactionmitochondrial_aldh_variant

Annotons

Mitochondrial K+-activated acetaldehyde dehydrogenase
mitochondrial_aldh_nad_activity
Participant: Family: aldehyde dehydrogenase family
Family:
aldehyde dehydrogenase familyPANTHER:PTHR11699
Representative Members: ALD4 (S. cerevisiae)UniProtKB:P46367
Required Function:
acetaldehyde dehydrogenase (NAD+) activityGO:0140087

Function

acetaldehyde dehydrogenase (NAD+) activityGO:0140087
Substrates: acetaldehyde NAD(+) H2O
Products: acetate NADH

Locations

mitochondrial matrixGO:0005759
Mitochondrial NADP+-dependent aldehyde dehydrogenase
mitochondrial_aldh_nadp_activity
Participant: Family: aldehyde dehydrogenase family
Family:
aldehyde dehydrogenase familyPANTHER:PTHR11699
Representative Members: ALD5 (S. cerevisiae)UniProtKB:P40047
Required Function:
acetaldehyde dehydrogenase (NADP+) activityGO:0140088

Function

acetaldehyde dehydrogenase (NADP+) activityGO:0140088
Substrates: acetaldehyde NADP(+) H2O
Products: acetate NADPH

Locations

mitochondrial matrixGO:0005759
Part 3: acetate activation
Acetate + ATP + CoA to acetyl-CoA + AMP + diphosphateReactionacetyl_coa_synthetase_step

Annotons

Acetyl-CoA synthetase (AMP-forming)
acs_activity
Participant: Family: AMP-forming acetyl-CoA synthetase
Family:
AMP-forming acetyl-CoA synthetasePANTHER:PTHR24095
Representative Members: ACS2 (S. cerevisiae)UniProtKB:P52910 ACS1 (S. cerevisiae)UniProtKB:Q01574 ACSS2 (human)UniProtKB:Q9NR19 acs (Escherichia coli K-12)UniProtKB:P27550
Required Function:
acetyl-CoA synthetase activityGO:0003987

Function

acetyl-CoA synthetase activityGO:0003987
Substrates: acetate ATP coenzyme A
Products: acetyl-CoA AMP diphosphate

Locations

cytosolGO:0005829 nucleusGO:0005634

The ATP-to-AMP step that makes the pathway irreversible and costs two phosphoanhydride bonds per acetyl-CoA. The acs1 acs2 double mutant is inviable (PMID:7649171).