Mevalonate pathway (acetyl-CoA -> isopentenyl diphosphate); statin target, mevalonate kinase deficiency

The mevalonate pathway is the cytosolic/ER route that converts acetyl-CoA into the universal five-carbon isoprenoid building block isopentenyl diphosphate (IPP), the precursor of cholesterol, dolichol, ubiquinone (CoQ), heme A, and the farnesyl/ geranylgeranyl groups used for protein prenylation. Cytosolic HMG-CoA synthase (HMGCS1) condenses acetoacetyl-CoA with acetyl-CoA to 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA); HMG-CoA reductase (HMGCR), the rate-limiting, committed, sterol-feedback-regulated enzyme and target of the statin drugs, reduces HMG-CoA to mevalonate using 2 NADPH on the endoplasmic-reticulum membrane; mevalonate kinase (MVK) and phosphomevalonate kinase (PMVK) then doubly phosphorylate mevalonate to mevalonate-5-diphosphate; and diphosphomevalonate decarboxylase (MVD) decarboxylates it to IPP. Inherited defects cause: mevalonate kinase deficiency (MVK) — spanning hyper-IgD/periodic fever syndrome to mevalonic aciduria; porokeratosis (MVD and MVK); and HMGCR/HMGCS1 are pharmacologic/ autoimmune (statin) and rare-myopathy loci rather than classic enzymopathies.

MODULE:mevalonate_pathwayDRAFTMetabolic Pathwaymodules/mevalonate_pathway.yaml

isopentenyl diphosphate biosynthetic process, mevalonate pathwayGO:0019287

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.

GO:0019287

isopentenyl diphosphate biosynthetic process, mevalonate pathway

The module is grounded in the GO isopentenyl diphosphate biosynthetic process, mevalonate pathway (GO:0019287): acetyl-CoA -> HMG-CoA -> mevalonate -> IPP.

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: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.

6Nodes

5Parts

0Variant Sets

0Variants

5Annotons

5Connections

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.

Gene-review completeness (5/5 grounded genes reviewed)

5 complete review(s) · 0 with deep research · 0 missing review · 5 reviewed but lacking deep research

Gene	Review	Complete	Deep research
HMGCR P04035	✓	✓	✗
HMGCS1 Q01581	✓	✓	✗
MVD P53602	✓	✓	✗
MVK Q03426	✓	✓	✗
PMVK Q15126	✓	✓	✗

Tree

Mevalonate pathway (-> IPP)Metabolic Pathwaymevalonate_pathway

Parts
1. 1. HMG-CoA synthesis
2. acetoacetyl-CoA + acetyl-CoA to (S)-HMG-CoA + CoAReactionhmgcs1_step
  
  Annotons
  - HMGCS1: HMG-CoA synthase (cytosolic) Family: HMG-CoA synthase family (HMGCS1/HMGCS2)
3. 2. rate-limiting reduction to mevalonate (statin target)
4. (S)-HMG-CoA + 2 NADPH to (R)-mevalonate + CoAReactionhmgcr_step
  
  Annotons
  - HMGCR: HMG-CoA reductase Family: HMG-CoA reductase family (HMGCR)
5. 3. mevalonate phosphorylation
6. (R)-mevalonate + ATP to (R)-mevalonate-5-phosphate + ADPReactionmvk_step
  
  Annotons
  - MVK: mevalonate kinase Family: Mevalonate kinase / GHMP kinase family (MVK)
7. 4. second phosphorylation
8. (R)-mevalonate-5-phosphate + ATP to (R)-mevalonate-5-diphosphate + ADPReactionpmvk_step
  
  Annotons
  - PMVK: phosphomevalonate kinase Family: Phosphomevalonate kinase family (PMVK)
9. 5. decarboxylation to isopentenyl diphosphate (IPP)
10. (R)-mevalonate-5-diphosphate + ATP to isopentenyl diphosphate + CO2 + ADP + PiReactionmvd_step
  
  Annotons
  - MVD: diphosphomevalonate decarboxylase Family: Diphosphomevalonate decarboxylase family (MVD)

Details

Context

cytosolGO:0005829

Mevalonate pathway (-> IPP)Metabolic Pathwaymevalonate_pathway

isopentenyl diphosphate biosynthetic process, mevalonate pathwayGO:0019287

Context

cytosolGO:0005829

The mevalonate pathway (acetyl-CoA -> IPP) grounded to the human enzymes HMGCS1 (UniProtKB:Q01581, GO:0004421, EC 2.3.3.10), HMGCR (P04035, GO:0004420, EC 1.1.1.34), MVK (Q03426, GO:0004496, EC 2.7.1.36), PMVK (Q15126, GO:0004631, EC 2.7.4.2) and MVD (P53602, GO:0004163, EC 4.1.1.33). GO molecular-function terms were taken from the human GOA records; Reactome reaction ids and titles were verified against the local reactome cache. Each step uses a PANTHER family selector (generic over orthologs; HMGCS node covers HMGCS1 cytosolic + HMGCS2 mitochondrial, the latter being the ketogenesis enzyme reviewed in the ketogenesis module). HMGCR is the sole ER-membrane step (sterol-regulated, statin target); the rest are cytosolic. Downstream, IPP is isomerised to dimethylallyl-PP (IDI1) and condensed by farnesyl/geranylgeranyl-PP synthases (FDPS/GGPS1) toward squalene -> cholesterol (post-squalene sterol synthesis: SQLE/LSS/.../SC5D/DHCR7/DHCR24), and also supplies dolichol, ubiquinone (CoQ), heme A and the prenyl groups for protein prenylation. Disorders: MVK -> mevalonate kinase deficiency (HIDS/periodic fever to mevalonic aciduria); MVD (and MVK) -> porokeratosis; HMGCR -> statin target and autoantibody-mediated necrotizing myopathy; HMGCS1 -> a rare rigid-spine myopathy. (Acetoacetyl-CoA for HMGCS1 is supplied by cytosolic thiolase ACAT2.) Regulation. The module has two regulatory nodes, not one. HMGCR is the sterol-feedback, SREBP/Insig-regulated rate-limiting step. MVK 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). That work reports inhibition kinetics and apo plus five inhibitor-bound X-ray structures for the *Saccharomyces cerevisiae* enzyme (ScMK) and states only that potency spans roughly two orders of magnitude; individual Ki values and the residue-level description of how one site accommodates C5-C20 ligands are not in the abstract, and the full text was not available here, so no numeric or structural detail beyond this is asserted. Whether the human MVK site behaves identically is likewise not established by that paper. No new module members follow from it - MVK is already part 3 - so the finding is recorded as a regulatory connection (mvd_step -| mvk_step) and annoton evidence rather than as an additional part.

Connections

hmgcs1_step -> hmgcr_step Provides Input For

HMG-CoA from HMGCS1 is reduced to mevalonate by HMGCR.

hmgcr_step -> mvk_step Provides Input For

Mevalonate from HMGCR is phosphorylated by MVK.

mvk_step -> pmvk_step Provides Input For

Mevalonate-5-phosphate from MVK is phosphorylated by PMVK.

pmvk_step -> mvd_step Provides Input For

Mevalonate-5-diphosphate from PMVK is decarboxylated by MVD to IPP.

mvd_step -> mvk_step Negatively Regulates

Feedback inhibition. IPP, the product of the MVD step, and the isoprenoid pyrophosphates derived from it further downstream (DMAPP via IDI1; 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: HMG-CoA synthesis

acetoacetyl-CoA + acetyl-CoA to (S)-HMG-CoA + CoAReactionhmgcs1_step

Annotons

HMGCS1: HMG-CoA synthase (cytosolic)

hmgcs1_activity

Participant: Family: HMG-CoA synthase family (HMGCS1/HMGCS2)

Family:

HMG-CoA synthase family (HMGCS1/HMGCS2)PANTHER:PTHR43323

Representative Members: HMGCS1 (human, cytosolic)UniProtKB:Q01581

Function

hydroxymethylglutaryl-CoA synthase activityGO:0004421

Substrates: acetoacetyl-CoA acetyl-CoA

Products: (S)-3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) CoA

Locations

cytosolGO:0005829

First committed cytosolic step: condenses acetoacetyl-CoA + acetyl-CoA to HMG-CoA (SREBP-regulated). Distinct from mitochondrial HMGCS2 of ketogenesis.

Part 2: rate-limiting reduction to mevalonate (statin target)

(S)-HMG-CoA + 2 NADPH to (R)-mevalonate + CoAReactionhmgcr_step

Annotons

HMGCR: HMG-CoA reductase

hmgcr_activity

Participant: Family: HMG-CoA reductase family (HMGCR)

Family:

HMG-CoA reductase family (HMGCR)PANTHER:PTHR10572

Representative Members: HMGCR (human)UniProtKB:P04035

Function

hydroxymethylglutaryl-CoA reductase (NADPH) activityGO:0004420

Substrates: (S)-HMG-CoA NADPH (x2)

Products: (R)-mevalonate CoA

Locations

endoplasmic reticulum membraneGO:0005789

Rate-limiting, committed enzyme of the pathway; polytopic ER-membrane protein with sterol-sensing domain and SREBP/Insig-regulated degradation. Target of the statin cholesterol-lowering drugs.

Part 3: mevalonate phosphorylation

(R)-mevalonate + ATP to (R)-mevalonate-5-phosphate + ADPReactionmvk_step

Annotons

MVK: mevalonate kinase

mvk_activity

Participant: Family: Mevalonate kinase / GHMP kinase family (MVK)

Family:

Mevalonate kinase / GHMP kinase family (MVK)PANTHER:PTHR43290

Representative Members: MVK (human)UniProtKB:Q03426

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). 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 4: second phosphorylation

(R)-mevalonate-5-phosphate + ATP to (R)-mevalonate-5-diphosphate + ADPReactionpmvk_step

Annotons

PMVK: phosphomevalonate kinase

pmvk_activity

Participant: Family: Phosphomevalonate kinase family (PMVK)

Family:

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

Phosphorylates mevalonate-5-phosphate to mevalonate-5-diphosphate (between MVK and MVD).

Part 5: decarboxylation to isopentenyl diphosphate (IPP)

(R)-mevalonate-5-diphosphate + ATP to isopentenyl diphosphate + CO2 + ADP + PiReactionmvd_step

Annotons

MVD: diphosphomevalonate decarboxylase

mvd_activity

Participant: Family: Diphosphomevalonate decarboxylase family (MVD)

Family:

Diphosphomevalonate decarboxylase family (MVD)PANTHER:PTHR10977

Representative Members: MVD (human)UniProtKB:P53602

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). Deficiency causes porokeratosis.