Mevalonate pathway (acetyl-CoA -> isopentenyl diphosphate)

The eukaryotic (classical) mevalonate pathway converts acetyl-CoA into the universal five-carbon isoprenoid building block isopentenyl diphosphate (IPP), the precursor of sterols (cholesterol in animals, ergosterol in fungi), dolichol, ubiquinone (CoQ), heme A and the farnesyl/geranylgeranyl groups used for protein prenylation. A cytosolic acetoacetyl-CoA thiolase condenses two acetyl-CoA to acetoacetyl-CoA; HMG-CoA synthase adds a third acetyl-CoA to give 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA); HMG-CoA reductase, the rate-limiting, sterol-feedback-regulated enzyme and target of the statin drugs, reduces HMG-CoA to mevalonate with two NADPH on the endoplasmic-reticulum membrane; mevalonate kinase and phosphomevalonate kinase then doubly phosphorylate mevalonate to mevalonate 5-diphosphate; and diphosphomevalonate decarboxylase decarboxylates it to IPP in an ATP-dependent reaction. The reaction chain is conserved across animals, fungi and plants, but the phosphomevalonate kinase step is carried out by two unrelated protein families: a GHMP-kinase-type enzyme (ERG8 type) in fungi, plants and bacteria, and a small P-loop kinase (PMVK type) that displaced it early in animal evolution. Fungi may carry two HMG-CoA reductase isozymes (budding yeast HMG1 and HMG2). Mevalonate kinase is a second, metabolite-level control point, competitively feedback-inhibited by downstream prenyl diphosphates. In humans, inherited defects cause mevalonate kinase deficiency (MVK; hyper-IgD/periodic fever syndrome to mevalonic aciduria) and porokeratosis (MVD and MVK); HMGCR and HMGCS1 are pharmacologic (statin), autoimmune and rare-myopathy loci rather than classic enzymopathies.

MODULE:mevalonate_pathwayDRAFTCONCRETEMetabolic Pathwaymodules/mevalonate_pathway.yaml
isopentenyl diphosphate biosynthetic process, mevalonate pathwayGO:0019287
GO:0019287
isopentenyl diphosphate biosynthetic process, mevalonate pathway
The module is grounded in the GO isopentenyl diphosphate biosynthetic process, mevalonate pathway (GO:0019287), defined as the conversion of acetate, in the form of acetyl-CoA, to IPP through mevalonate intermediates; the acetoacetyl-CoA thiolase step is therefore inside the boundary.
YeastPathways:IPPSYN-PWY
mevalonate pathway (S. cerevisiae, SGD YeastPathways)
YeastCyc lists ERG10, ERG13, HMG1/HMG2, ERG12, ERG8, MVD1 and IDI1 as the catalysts of the mevalonate pathway. All gene assignments were retained; IDI1 (IPP/DMAPP isomerase) is modelled in the downstream isoprenoid_diphosphate_biosynthesis module because GO:0019287 ends at IPP.
YeastPathways:PWY-922
mevalonate pathway I (S. cerevisiae, SGD YeastPathways)
Duplicate YeastCyc frame with the same seven reactions and gene list as IPPSYN-PWY.
PMID:42754161
Structural basis of mevalonate pathway regulation by feedback inhibition of mevalonate kinase.
Mevalonate kinase is a second regulatory node of the pathway (alongside the sterol-regulated HMGCR step): downstream isoprenoid pyrophosphates feedback-inhibit MVK, and the five known inhibitors (IPP, DMAPP, GPP, FPP, GGPP) compete for one shared site despite spanning C5-C20.
Mevalonate kinase (MK) catalyzes a key regulatory step of mevalonate pathway in many eukaryotes, in which several downstream isoprenoid pyrophosphates act as feedback inhibitors.
PMID:41700894
Harnessing evolution: leveraging bacterial isoprenoid pathway diversity toward improved bioengineering strategies.
2026 review used to audit the module's scope. It separates the eukaryotic/bacterial-type mevalonate pathway modeled here from archaeal-type routes, which some Chloroflexota bacteria also carry, and distinguishes type I from type II HMG-CoA reductases. Those variants are recorded in notes; they are not modeled as variants.
There is a eukaryotic/bacterial-type MEV pathway and an archaeal-type MEV pathway, which differ in the intermediate steps taken, but ultimately both lead to the generation of IDP and DMADP (40, 63).
PMID:24327557
Discovery of a metabolic alternative to the classical mevalonate pathway.
Primary evidence for the alternative route in which mevalonate 5-phosphate is decarboxylated (MPD) to isopentenyl phosphate and then phosphorylated by isopentenyl phosphate kinase (IPK). It replaces the PMVK and MVD steps of this module in Haloferax and some Chloroflexi.
Key to this pathway is the catalytic actions of a newly uncovered enzyme, mevalonate phosphate decarboxylase (MPD) and IPK.
PMID:16621811
Methanocaldococcus jannaschii uses a modified mevalonate pathway for biosynthesis of isopentenyl diphosphate.
Primary identification of archaeal isopentenyl phosphate kinase (MJ0044), which was predicted to be the missing phosphomevalonate kinase but phosphorylates isopentenyl phosphate instead.
The MJ0044 gene product was found to phosphorylate isopentenyl phosphate, generating isopentenyl diphosphate.
PMID:24914732
Evidence of a novel mevalonate pathway in archaea.
Thermoplasma acidophilum mevalonate-3-kinase and mevalonate-3-phosphate-5-kinase define a third, 3-phosphorylating archaeal route from mevalonate toward IPP.
We have identified two novel enzymes, mevalonate-3-kinase and mevalonate-3-phosphate-5-kinase from Thermoplasma acidophilum, which act sequentially in a putative alternate mevalonate pathway.
PMID:7989303
ERG10 from Saccharomyces cerevisiae encodes acetoacetyl-CoA thiolase.
ERG10 is the single-copy essential gene for the cytoplasmic acetoacetyl-CoA thiolase; erg10 and hmg1 alleles were recovered as mevalonate auxotrophs.
null alleles of ERG10 produced no detectable acetoacetyl-CoA thiolase enzyme activity
PMID:3526336
Saccharomyces cerevisiae contains two functional genes encoding 3-hydroxy-3-methylglutaryl-coenzyme A reductase.
Budding yeast has two HMG-CoA reductase genes, HMG1 and HMG2, homologous to the catalytic carboxy-terminal half of the animal enzyme; loss of both is lethal and HMG1 contributes most of the activity.
HMG1 contributes at least 83% of the activity found in wild-type cells
PMID:1645230
Nucleotide sequence of the ERG12 gene of Saccharomyces cerevisiae encoding mevalonate kinase.
ERG12 encodes yeast mevalonate kinase; the enzyme is not rate-limiting but is sensitive to farnesyl diphosphate, an early report of the feedback control later resolved structurally (PMID:42754161).
we show that mevalonate kinase is not a rate-limiting enzyme; however its sensitivity to FFP could be a key regulatory mechanism in the sterol pathway of yeast.
PMID:1846667
Cloning and characterization of ERG8, an essential gene of Saccharomyces cerevisiae that encodes phosphomevalonate kinase.
ERG8 is an essential, single-copy gene encoding yeast phosphomevalonate kinase.
Expression of the ERG8 gene in S. cerevisiae from the galactose-inducible galactokinase (GAL1) promoter resulted in 1,000-fold-elevated levels of phosphomevalonate kinase enzyme activity.
PMID:11243736
Nonorthologous gene displacement of phosphomevalonate kinase.
ERG8-type phosphomevalonate kinases (eubacteria, fungi, plants) and the animal PMVK are nonorthologous, justifying the phosphomevalonate-kinase variant set.
orthologues of ERG8 are present in eubacteria, fungi, and plants, while orthologues of human PMK are found only in animals, indicative of a nonorthologous gene displacement early in animal evolution
PMID:8663599
Molecular cloning of human phosphomevalonate kinase and identification of a consensus peroxisomal targeting sequence.
The animal-type phosphomevalonate kinase is a small (191-residue) protein.
The human PMKase cDNAs predict a 191-amino acid protein
PMID:8626466
Molecular cloning and expression of the cDNAs encoding human and yeast mevalonate pyrophosphate decarboxylase.
Human and yeast diphosphomevalonate decarboxylases are orthologous and were cloned and expressed together.
We also cloned and expressed the yeast homolog using the human enzyme's similarity to a previously unidentified and incomplete genomic sequence.
PMID:32679672
Regulation of Ergosterol Biosynthesis in Saccharomyces cerevisiae.
Review of the yeast sterol pathway, including the mevalonate segment, and its transcriptional and feedback regulation.
Reactome:R-HSA-191273
Cholesterol biosynthesis
Step order and reaction stoichiometries follow the human Reactome cholesterol/ isoprenoid-biosynthesis reactions R-HSA-191323 (HMGCS1), R-HSA-191352 (HMGCR), R-HSA-191380 (MVK), R-HSA-191422 (PMVK) and R-HSA-191414 (MVD).
file:yeast/ERG10/ERG10-ai-review.yaml
ERG10 gene review (S. cerevisiae)
The acetoacetyl-CoA thiolase step (UniProtKB:P41338, GO:0003985, cytosol, directly involved in GO:0019287 and ergosterol biosynthesis) matches the core function of the ERG10 review.
file:human/HMGCS1/HMGCS1-ai-review.yaml
HMGCS1 gene review (human)
The HMG-CoA-synthesis step (UniProtKB:Q01581, GO:0004421) matches the completed human HMGCS1 review.
file:human/HMGCR/HMGCR-ai-review.yaml
HMGCR gene review (human)
The rate-limiting HMG-CoA-reductase step (UniProtKB:P04035, GO:0004420) matches the completed human HMGCR review.
file:human/MVK/MVK-ai-review.yaml
MVK gene review (human)
The mevalonate-kinase step (UniProtKB:Q03426, GO:0004496) matches the completed human MVK review.
file:human/PMVK/PMVK-ai-review.yaml
PMVK gene review (human)
The phosphomevalonate-kinase step (UniProtKB:Q15126, GO:0004631) matches the completed human PMVK review.
file:human/MVD/MVD-ai-review.yaml
MVD gene review (human)
The diphosphomevalonate-decarboxylase step (UniProtKB:P53602, GO:0004163) matches the completed human MVD review.
9Nodes
6Parts
1Variant Sets
2Variants
7Annotons
6Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

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

Leaf nodes lacking representative members

✓ every leaf node grounds to a representative protein.

Template conformance

✓ every declared conforms_to bundle matches its template motif.

Reaction chaining (advisory)

✓ every PRECEDES step chains, or its break is acknowledged via chaining_status.

  • thiolase_step → hmgcs1_step [VERIFIED]
    shared: acetoacetylcoa, acetylcoa, coa
  • hmgcs1_step → hmgcr_step [VERIFIED]
    shared: 3s3hydroxy3methylglutarylcoa, coa
  • hmgcr_step → mvk_step [NOT_CHECKED]
  • mvk_step → pmvk_step [NOT_CHECKED]
  • pmvk_step → mvd_step [NOT_CHECKED]

Function consistency and core coverage

18 gene-function check(s) reflected in core functions · 0 conflict(s) · 1 evidence or coverage gap(s) (26 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
thiolase_activity ERG10 (Saccharomyces cerevisiae)
UniProtKB:P41338
Family Representative 		acetyl-CoA C-acetyltransferase activity
GO:0003985 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
thiolase_activity erg10 (Schizosaccharomyces pombe)
UniProtKB:Q9UQW6
Family Representative 		acetyl-CoA C-acetyltransferase activity
GO:0003985 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
thiolase_activity ACAT2 (human, cytosolic)
UniProtKB:Q9BWD1
Family Representative 		acetyl-CoA C-acetyltransferase activity
GO:0003985 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
hmgcs1_activity HMGCS1 (human, cytosolic)
UniProtKB:Q01581
Family Representative 		hydroxymethylglutaryl-CoA synthase activity
GO:0004421 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
hmgcs1_activity ERG13 (Saccharomyces cerevisiae)
UniProtKB:P54839
Family Representative 		hydroxymethylglutaryl-CoA synthase activity
GO:0004421 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
hmgcs1_activity hcs1 (Schizosaccharomyces pombe)
UniProtKB:P54874
Family Representative 		hydroxymethylglutaryl-CoA synthase activity
GO:0004421 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
hmgcr_activity HMGCR (human)
UniProtKB:P04035
Family Representative 		hydroxymethylglutaryl-CoA reductase (NADPH) activity
GO:0004420 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
hmgcr_activity HMG1 (Saccharomyces cerevisiae; major isozyme)
UniProtKB:P12683
Family Representative 		hydroxymethylglutaryl-CoA reductase (NADPH) activity
GO:0004420 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
hmgcr_activity HMG2 (Saccharomyces cerevisiae; minor isozyme)
UniProtKB:P12684
Family Representative 		hydroxymethylglutaryl-CoA reductase (NADPH) activity
GO:0004420 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
hmgcr_activity hmg1 (Schizosaccharomyces pombe)
UniProtKB:Q10283
Family Representative 		hydroxymethylglutaryl-CoA reductase (NADPH) activity
GO:0004420 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
mvk_activity MVK (human)
UniProtKB:Q03426
Family Representative 		mevalonate kinase activity
GO:0004496 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
mvk_activity ERG12 (Saccharomyces cerevisiae)
UniProtKB:P07277
Family Representative 		mevalonate kinase activity
GO:0004496 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
mvk_activity erg12 (Schizosaccharomyces pombe)
UniProtKB:Q09780
Family Representative 		mevalonate kinase activity
GO:0004496 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
erg8_pmk_activity ERG8 (Saccharomyces cerevisiae)
UniProtKB:P24521
Family Representative 		phosphomevalonate kinase activity
GO:0004631 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
erg8_pmk_activity erg8 (Schizosaccharomyces pombe)
UniProtKB:Q9UT88
Family Representative 		phosphomevalonate kinase activity
GO:0004631 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
pmvk_activity PMVK (human)
UniProtKB:Q15126
Family Representative 		phosphomevalonate kinase activity
GO:0004631 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
mvd_activity MVD (human)
UniProtKB:P53602
Family Representative 		diphosphomevalonate decarboxylase activity
GO:0004163 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
mvd_activity MVD1 (Saccharomyces cerevisiae)
UniProtKB:P32377
Family Representative 		diphosphomevalonate decarboxylase activity
GO:0004163 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
mvd_activity mvd1 (Schizosaccharomyces pombe)
UniProtKB:O13963
Family Representative 		diphosphomevalonate decarboxylase activity
GO:0004163 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
thiolase_activity Cytosolic acetoacetyl-CoA thiolase (ERG10 / ACAT2)
PANTHER:PTHR18919
Family 		acetyl-CoA C-acetyltransferase activity
GO:0003985 		Family Supported
Family review supports GO:0003985 FAMILY_WIDE. Asserted by mevalonate_pathway and ketogenesis. It is the defining activity of the acetoacetyl-CoA thiolase subfamilies, and the long-chain thiolases also act on acetoacetyl-CoA, which is why their reviews retain it as non-core.
hmgcs1_activity HMG-CoA synthase family (HMGCS1/HMGCS2, ERG13)
PANTHER:PTHR43323
Family 		hydroxymethylglutaryl-CoA synthase activity
GO:0004421 		Family Supported
Family review supports GO:0004421 FAMILY_WIDE. Asserted by mevalonate_pathway and ketogenesis; accepted by every reviewed member.
hmgcr_activity Class I HMG-CoA reductase family (HMGCR, HMG1/HMG2)
PANTHER:PTHR10572
Family 		hydroxymethylglutaryl-CoA reductase (NADPH) activity
GO:0004420 		Family Supported
Family review supports GO:0004420 FAMILY_WIDE. Asserted by mevalonate_pathway; accepted by S. cerevisiae HMG1/HMG2, S. pombe hmg1 and human HMGCR.
mvk_activity Mevalonate kinase / GHMP kinase family (MVK, ERG12)
PANTHER:PTHR43290
Family 		mevalonate kinase activity
GO:0004496 		Family Supported
Family review supports GO:0004496 FAMILY_WIDE. Asserted by mevalonate_pathway; accepted by MVK, ERG12 and erg12.
erg8_pmk_activity ERG8-type (GHMP) phosphomevalonate kinase family
PANTHER:PTHR31814
Family 		phosphomevalonate kinase activity
GO:0004631 		Family Supported
Family review supports GO:0004631 FAMILY_WIDE. Asserted by mevalonate_pathway; accepted by ERG8 and erg8.
pmvk_activity Animal phosphomevalonate kinase family (PMVK)
PANTHER:PTHR13101
Family 		phosphomevalonate kinase activity
GO:0004631 		Family Supported
Family review supports GO:0004631 FAMILY_WIDE. Asserted by mevalonate_pathway; accepted by human PMVK.
mvd_activity Diphosphomevalonate decarboxylase family (MVD, MVD1)
PANTHER:PTHR10977
Family 		diphosphomevalonate decarboxylase activity
GO:0004163 		Family Supported
Family review supports GO:0004163 FAMILY_WIDE. Asserted by mevalonate_pathway; accepted by MVD1, mvd1 and MVD.

Feedback loops (advisory, prose-driven: a regulator counts as "feedback" when its own description says so)

✓ every negative regulator described as feedback has an upstream edge closing the loop.

  • mvd_step ⊣ mvk_step [closed]
    mvd_step is regulated by pmvk_step: feedback loop closed

Gene-review completeness (18/19 grounded genes reviewed)

17 complete review(s) · 7 with deep research · 1 missing review · 11 reviewed but lacking deep research

Gene Review Complete Deep research
ERG10 P41338 ✓ ✓ ✓
erg10 Q9UQW6 ✓ ✓ ✗
ERG12 P07277 ✓ ✓ ✓
erg12 Q09780 ✓ ✓ ✗
ERG13 P54839 ✓ ✓ ✓
ERG19 P32377 ✓ ✓ ✓
ERG8 P24521 ✓ ✓ ✓
erg8 Q9UT88 ✓ 12/14 ✗
hcs1 P54874 ✓ ✓ ✗
HMG1 P12683 ✓ ✓ ✓
hmg1 Q10283 ✓ ✓ ✗
HMG2 P12684 ✓ ✓ ✓
HMGCR P04035 ✓ ✓ ✗
HMGCS1 Q01581 ✓ ✓ ✗
MVD P53602 ✓ ✓ ✗
mvd1 O13963 ✓ ✓ ✗
MVK Q03426 ✓ ✓ ✗
PMVK Q15126 ✓ ✓ ✗
ACAT2 (human, cytosolic) Q9BWD1 ✗ — —

Details

Context
cytosolGO:0005829
Mevalonate pathway (acetyl-CoA -> IPP)Metabolic Pathwaymevalonate_pathway
isopentenyl diphosphate biosynthetic process, mevalonate pathwayGO:0019287
Context
cytosolGO:0005829

Generalised from a human-only module to the eukaryotic (classical) mevalonate pathway. Changes: (1) the cytosolic acetoacetyl-CoA thiolase step was added as part 1, because GO:0019287 is defined from acetyl-CoA, YeastCyc IPPSYN-PWY and both yeast GO-CAMs include it, and the ERG10 review places ERG10 directly in GO:0019287; the human representative is the cytosolic ACAT2 (UniProtKB:Q9BWD1), not the mitochondrial ACAT1 of ketone-body metabolism. (2) S. cerevisiae (ERG10, ERG13, HMG1, HMG2, ERG12, ERG8, MVD1) and S. pombe (erg10, hcs1, hmg1, erg12, erg8, mvd1) representatives were added; all share the human enzymes' PANTHER families except phosphomevalonate kinase. (3) The phosphomevalonate kinase step became a variant set: ERG8-type GHMP kinases (PTHR31814; fungi, plants, eubacteria) and the animal P-loop PMVK (PTHR13101) are nonorthologous (PMID:11243736), so one family selector cannot cover both. (4) Connections were retyped from PROVIDES_INPUT_FOR to PRECEDES. IDI1, which both YeastCyc frames list, is modelled in isoprenoid_diphosphate_biosynthesis (IPP -> DMAPP), because the GO process term ends at IPP. Archaeal variants of the lower mevalonate pathway are outside this module. Regulation. HMG-CoA reductase is the sterol-feedback, rate-limiting step (SREBP/Insig in animals; the PomBase model also records the ppe1 phosphatase and its inhibitor sds23 acting upstream of S. pombe hmg1). Mevalonate kinase is a second, metabolite-level control point: downstream isoprenoid pyrophosphates feedback-inhibit it, and the five known inhibitors (IPP, DMAPP, GPP, FPP, GGPP) compete for one shared site despite spanning C5-C20 (PMID:42754161, which reports inhibition kinetics and apo plus five inhibitor-bound X-ray structures for the S. cerevisiae enzyme; per-inhibitor Ki values are not in the abstract and are not asserted). FPP sensitivity of yeast ERG12 was already reported in PMID:1645230. GO-CAM disagreements: both SGD conversions place every activity, including the ER-membrane HMG1/HMG2, in cytosol, give HMG1 and HMG2 one shared activity IRI, and use either the broad GO:0008299 or the obsolete GO:0010142 as the process; the PomBase model uses GO:0010142 and GO:0045337 rather than GO:0019287 as process terms. Human disorders: MVK -> mevalonate kinase deficiency; MVD (and MVK) -> porokeratosis; HMGCR -> statin target and autoantibody-mediated necrotizing myopathy; HMGCS1 -> a rare rigid-spine myopathy. Scope against mevalonate-pathway diversity (2026 review PMID:41700894). This module models the eukaryotic/bacterial-type route (MVK -> PMVK -> MVD). Archaea and some Chloroflexota use archaeal-type variants that share HMGCS/HMGCR chemistry up to mevalonate and then diverge. In one, mevalonate 5-phosphate is decarboxylated to isopentenyl phosphate and phosphorylated by isopentenyl phosphate kinase (PMID:24327557, PMID:16621811). In Thermoplasma the route goes through mevalonate 3-phosphate and mevalonate 3,5-bisphosphate (PMID:24914732). These are not modeled as variants here, and the human representatives and PANTHER selectors for the PMVK and MVD steps should not be read as covering archaea. HMG-CoA reductase also comes as type I (eukaryotes, archaea, some bacteria) and type II (mostly bacteria), which differ in statin sensitivity. PANTHER:PTHR10572 contains both, including the NAD-dependent class II enzyme of Pseudomonas mevalonii (UniProtKB:P13702, EC 1.1.1.88). The family-level GO:0004420 (NADPH) assertion is therefore exact only for the class I members represented here.

Connections

Acetoacetyl-CoA from the thiolase is condensed with acetyl-CoA by HMG-CoA synthase.
hmgcs1_step -> hmgcr_step Precedes
HMG-CoA from HMG-CoA synthase is reduced to mevalonate by HMG-CoA reductase.
hmgcr_step -> mvk_step Precedes
Mevalonate from HMG-CoA reductase is phosphorylated by mevalonate kinase.
mvk_step -> pmvk_step Precedes
Mevalonate-5-phosphate is phosphorylated by phosphomevalonate kinase.
pmvk_step -> mvd_step Precedes
Mevalonate-5-diphosphate is decarboxylated to IPP.
mvd_step -> mvk_step Negatively Regulates
Feedback inhibition. IPP, the product of the decarboxylase step, and the isoprenoid pyrophosphates derived from it further downstream (DMAPP via IPP isomerase; GPP, FPP and GGPP via the prenyltransferases) competitively inhibit mevalonate kinase at a single shared site, closing a negative-feedback loop on the pathway's first phosphorylation step.
PMID:42754161
Structural basis of mevalonate pathway regulation by feedback inhibition of mevalonate kinase.
Downstream isoprenoid pyrophosphates act as feedback inhibitors of the mevalonate kinase step.
Mevalonate kinase (MK) catalyzes a key regulatory step of mevalonate pathway in many eukaryotes, in which several downstream isoprenoid pyrophosphates act as feedback inhibitors.
Part 1: acetoacetyl-CoA formation (thiolase)
2 acetyl-CoA to acetoacetyl-CoA + CoAReactionthiolase_step

Annotons

cytosolic acetoacetyl-CoA thiolase
thiolase_activity
Participant: Family: Cytosolic acetoacetyl-CoA thiolase (ERG10 / ACAT2)
Family:
Cytosolic acetoacetyl-CoA thiolase (ERG10 / ACAT2)PANTHER:PTHR18919 The PANTHER family covers all thiolases, including mitochondrial and peroxisomal 3-ketoacyl-CoA thiolases of beta-oxidation; the mevalonate role belongs to the cytosolic acetoacetyl-CoA thiolase members shown as representatives (ERG10 in PTHR18919:SF165, human ACAT2 in PTHR18919:SF107).
Representative Members: ERG10 (Saccharomyces cerevisiae)UniProtKB:P41338 erg10 (Schizosaccharomyces pombe)UniProtKB:Q9UQW6 ACAT2 (human, cytosolic)UniProtKB:Q9BWD1

Function

acetyl-CoA C-acetyltransferase activityGO:0003985
Substrates: acetyl-CoA (x2)
Products: acetoacetyl-CoA CoA

Locations

cytosolGO:0005829

Claisen condensation of two acetyl-CoA to acetoacetyl-CoA, the substrate of HMG-CoA synthase. In animals the cytosolic isozyme ACAT2 serves this role, distinct from the mitochondrial ACAT1 of ketone-body metabolism.

Part 2: HMG-CoA synthesis
acetoacetyl-CoA + acetyl-CoA to (S)-HMG-CoA + CoAReactionhmgcs1_step

Annotons

HMG-CoA synthase (cytosolic)
hmgcs1_activity
Participant: Family: HMG-CoA synthase family (HMGCS1/HMGCS2, ERG13)
Family:
HMG-CoA synthase family (HMGCS1/HMGCS2, ERG13)PANTHER:PTHR43323
Representative Members: HMGCS1 (human, cytosolic)UniProtKB:Q01581 ERG13 (Saccharomyces cerevisiae)UniProtKB:P54839 hcs1 (Schizosaccharomyces pombe)UniProtKB:P54874

Function

hydroxymethylglutaryl-CoA synthase activityGO:0004421
Substrates: acetoacetyl-CoA acetyl-CoA
Products: (S)-3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) CoA

Locations

cytosolGO:0005829

Condenses acetoacetyl-CoA + acetyl-CoA to HMG-CoA (SREBP-regulated in animals). Distinct from mitochondrial HMGCS2 of ketogenesis, which is in the same PANTHER family.

Part 3: rate-limiting reduction to mevalonate (statin target)
(S)-HMG-CoA + 2 NADPH to (R)-mevalonate + CoAReactionhmgcr_step

Annotons

HMG-CoA reductase (class I)
hmgcr_activity
Participant: Family: Class I HMG-CoA reductase family (HMGCR, HMG1/HMG2)
Family:
Class I HMG-CoA reductase family (HMGCR, HMG1/HMG2)PANTHER:PTHR10572
Representative Members: HMGCR (human)UniProtKB:P04035 HMG1 (Saccharomyces cerevisiae; major isozyme)UniProtKB:P12683 HMG2 (Saccharomyces cerevisiae; minor isozyme)UniProtKB:P12684 hmg1 (Schizosaccharomyces pombe)UniProtKB:Q10283

Function

hydroxymethylglutaryl-CoA reductase (NADPH) activityGO:0004420
Substrates: (S)-HMG-CoA NADPH (x2)
Products: (R)-mevalonate CoA

Locations

endoplasmic reticulum membraneGO:0005789

Rate-limiting enzyme of the pathway; polytopic ER-membrane protein with a sterol-sensing domain. Animal HMGCR is regulated by SREBP/Insig and sterol-accelerated degradation and is the statin target; budding yeast has two partially redundant isozymes, of which HMG1 contributes most of the activity (PMID:3526336).

Part 4: mevalonate phosphorylation
(R)-mevalonate + ATP to (R)-mevalonate-5-phosphate + ADPReactionmvk_step

Annotons

mevalonate kinase (GHMP kinase)
mvk_activity
Participant: Family: Mevalonate kinase / GHMP kinase family (MVK, ERG12)
Family:
Mevalonate kinase / GHMP kinase family (MVK, ERG12)PANTHER:PTHR43290
Representative Members: MVK (human)UniProtKB:Q03426 ERG12 (Saccharomyces cerevisiae)UniProtKB:P07277 erg12 (Schizosaccharomyces pombe)UniProtKB:Q09780

Function

mevalonate kinase activityGO:0004496
Substrates: (R)-mevalonate ATP
Products: (R)-mevalonate 5-phosphate ADP

Locations

cytosolGO:0005829

Phosphorylates mevalonate to mevalonate-5-phosphate. Second regulatory node of the pathway: competitively feedback-inhibited at a single shared site by downstream isoprenoid pyrophosphates spanning C5-C20 (IPP, DMAPP, GPP, FPP, GGPP). Human deficiency causes mevalonate kinase deficiency (hyper-IgD/periodic fever to mevalonic aciduria).

PMID:42754161
Structural basis of mevalonate pathway regulation by feedback inhibition of mevalonate kinase.
All five known isoprenoid-pyrophosphate feedback inhibitors of mevalonate kinase compete for a single binding site despite ranging from C5 to C20.
Known MK inhibitors vary widely in size, including IPP and DMAPP (five carbons, C5), geranyl pyrophosphate (GPP, C10), farnesyl pyrophosphate (FPP, C15), and geranylgeranyl pyrophosphate (GGPP, C20). These inhibitors compete for binding at a single site
PMID:42754161
Structural basis of mevalonate pathway regulation by feedback inhibition of mevalonate kinase.
Inhibition kinetics and apo/inhibitor-bound crystal structures were determined for the Saccharomyces cerevisiae enzyme (ScMK); inhibitor potencies span roughly two orders of magnitude. Per-inhibitor Ki values are not stated in the abstract and are deliberately not recorded here.
we first characterized the inhibition kinetics of all five of these inhibitors using MK from Saccharomyces cerevisiae (ScMK), revealing an inhibition potency that ranges approximately two orders of magnitude
Part 5: second phosphorylation
(R)-mevalonate-5-phosphate + ATP to (R)-mevalonate-5-diphosphate + ADPReactionpmvk_step
Variant set: Phosphomevalonate kinase protein families by enzyme family (nonorthologous gene displacement) (Exactly One)
PMID:11243736
Nonorthologous gene displacement of phosphomevalonate kinase.
The two phosphomevalonate kinase families differ in their ATP-binding motifs and phylogenetic distribution.
a protein kinase motif in the ERG8 orthologues versus a P-loop or Walker A motif in the animal orthologues
GHMP-type phosphomevalonate kinase (ERG8 type; fungi, plants, bacteria)Reactionghmp_erg8_pmk_variant

Annotons

ERG8-type phosphomevalonate kinase
erg8_pmk_activity
Participant: Family: ERG8-type (GHMP) phosphomevalonate kinase family
Family:
ERG8-type (GHMP) phosphomevalonate kinase familyPANTHER:PTHR31814 PANTHER leaves the family unnamed; its subfamily PTHR31814:SF2 is named PHOSPHOMEVALONATE KINASE and contains both yeast representatives.
Representative Members: ERG8 (Saccharomyces cerevisiae)UniProtKB:P24521 erg8 (Schizosaccharomyces pombe)UniProtKB:Q9UT88

Function

phosphomevalonate kinase activityGO:0004631
Substrates: (R)-mevalonate 5-phosphate ATP
Products: (R)-mevalonate 5-diphosphate ADP

Locations

cytosolGO:0005829

GHMP-kinase-type phosphomevalonate kinase, ancestral form present in fungi, plants and eubacteria.

P-loop phosphomevalonate kinase (PMVK type; animals)Reactionanimal_pmvk_variant

Annotons

PMVK: phosphomevalonate kinase
pmvk_activity
Participant: Family: Animal phosphomevalonate kinase family (PMVK)
Family:
Animal phosphomevalonate kinase family (PMVK)PANTHER:PTHR13101
Representative Members: PMVK (human)UniProtKB:Q15126

Function

phosphomevalonate kinase activityGO:0004631
Substrates: (R)-mevalonate 5-phosphate ATP
Products: (R)-mevalonate 5-diphosphate ADP

Locations

cytosolGO:0005829

Small P-loop (Walker A) kinase that replaced the ERG8-type enzyme early in animal evolution; carries a C-terminal PTS1-like sequence (PMID:8663599).

Part 6: decarboxylation to isopentenyl diphosphate (IPP)
(R)-mevalonate-5-diphosphate + ATP to isopentenyl diphosphate + CO2 + ADP + PiReactionmvd_step

Annotons

diphosphomevalonate decarboxylase
mvd_activity
Participant: Family: Diphosphomevalonate decarboxylase family (MVD, MVD1)
Family:
Diphosphomevalonate decarboxylase family (MVD, MVD1)PANTHER:PTHR10977
Representative Members: MVD (human)UniProtKB:P53602 MVD1 (Saccharomyces cerevisiae)UniProtKB:P32377 mvd1 (Schizosaccharomyces pombe)UniProtKB:O13963

Function

diphosphomevalonate decarboxylase activityGO:0004163
Substrates: (R)-mevalonate 5-diphosphate ATP
Products: isopentenyl diphosphate (IPP) CO2 + ADP + phosphate

Locations

cytosolGO:0005829

Final step: ATP-dependent decarboxylation of mevalonate-5-diphosphate to the C5 isoprenoid unit isopentenyl diphosphate (IPP). Human deficiency causes porokeratosis.