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
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
4Connections

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 ✓ ✓ ✗

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.)

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.
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. Deficiency causes mevalonate kinase deficiency (hyper-IgD/periodic fever to mevalonic aciduria).

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.