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Genemoderate confidence 3 of 5: One strong study, or several smaller consistent ones.Q109-serine-one-carbon

PSPH (P78330) - the third serine-synthesis enzyme, high in Ewing sarcoma alongside PHGDH and PSAT1, and the one that does NOT fall in leukaemia

also called phosphoserine phosphatase · SERB_HUMAN · PSP

PSPH does the final, irreversible step that actually releases serine. In Ewing sarcoma it is switched on alongside the two enzymes before it, and a menin inhibitor switches all three down. In KMT2A-rearranged leukaemia the first two collapse and PSPH barely moves - so the three-enzyme pathway is not controlled as one unit here.

The same thing, for a scientist

PSPH (P78330, 225 aa, exactly one reviewed human record, no UniProt synonyms) catalyses the last, irreversible step of serine biosynthesis, dephosphorylating O-phospho-L-serine, and the serine released feeds protein synthesis, other amino acids, nucleotide metabolism, glutathione, or racemisation to the neuromodulator D-serine [E3]. **The measurement that earns this entry is a near-null:** RS4;11 day 7, VTP-50469 **-0.48** from a detected baseline of 5.72 log2 CPM, EPZ5676 -0.47, margin **-0.01**; MOLM13 -0.31; MV4;11 -0.64 from a baseline of 2.45; array probes -0.51 (baseline 7.88) and -0.20 (11.37) in RS4;11 [E1]. **It was excluded from the serine arm by the pre-declared 1 log2 rule, and that exclusion is the finding.** PMID 29672864 names the SSP genes whose baseline expression and flux are high in Ewing sarcoma as **PHGDH, PSAT1 and PSPH**, and reports all of them diminished by menin inhibition [E4]. In KMT2A-rearranged B-ALL the first two fall 3.24 and 2.40 log2 and the third falls 0.48. **So the 'core serine synthesis pathway' does not behave as a unit in this disease**, and any claim in this graph phrased at pathway level is wrong for one of its three canonical members. DepMap: mean **-0.1161, 0.6% of 1,258 below -0.5** [E2]. Germline biallelic loss causes phosphoserine phosphatase deficiency with pre- and postnatal growth retardation [E3].

Go deeper
Three enzymes, one pathway, three different behaviours

RS4;11 day 7, same samples, same assay 1:

enzymestepVTP-50469EPZ5676marginbaseline
PHGDH1, rate-limiting-3.24-1.52-1.727.61
PSAT12, transamination-2.40-1.85-0.558.35
PSPH3, irreversible release-0.48-0.47-0.015.72

PSPH is expressed (5.72 log2 CPM, above the declared 1.0 floor; 7.88 and 11.37 log2 RMA on two array probes, above the 6.0 floor) so this is a measured null and not a detection failure.

Two consequences. First, the pathway-level phrasing has to go: a reader who takes "menin inhibition collapses the serine synthesis pathway" and predicts PSPH will be wrong by 2.8 log2. Second, it sharpens the mechanism question - a single transcription factor acting on a co-regulated three-gene cassette cannot give -3.24, -2.40 and -0.48, whereas a locus-by-locus chromatin input can.

Whether serine OUTPUT actually falls is a separate question this entry cannot answer: PSPH catalyses the committed release step, so an unchanged PSPH with a collapsed PHGDH means the pathway's entrance is shut and its exit is not, and only a flux measurement distinguishes a shut pathway from a redirected one.

Facts and figures
gene symbolPSPH
uniprotP78330
length AA225
entry nameSERB_HUMAN
protein namePhosphoserine phosphatase
ensembl gene IDENSG00000146733
ensembl readbackdisplay_name read back as PSPH before use
accession resolutiongene_exact:PSPH AND organism_id:9606 AND reviewed:true returns EXACTLY ONE reviewed row (rule 62 asserted): P78330, SERB_HUMAN, gene_primary PSPH, no synonyms, 225 aa.
localizationCYTOPLASM/CYTOSOL, INFERRED NOT MEASURED. UniProt P78330's single SUBCELLULAR LOCATION statement carries ECO:0000305 (curator inference) citing PubMed 1965857, a 1990 partial purification of phosphoserine phosphatase from human brain. Same shape as MTHFD1's record. No localisation experiment on PSPH has been performed in any KMT2A-rearranged cell.
subcellular localizationCYTOSOLIC by curator inference. Of the three canonical serine-synthesis enzymes, PSPH is the only one with any compartment statement at all - PHGDH (O43175) and PSAT1 (Q9Y617) have none - and PSPH's is an inference.
subnuclear localizationNONE, answered negative rather than left blank: no nuclear pool is annotated or reported for PSPH.
cell typeRS4;11 and SEM (KMT2A::AFF1 B-ALL), REH (KMT2A wild type), MOLM13 (KMT2A::MLLT3 AML) and MV4;11 (KMT2A::AFF1 myeloid) measured here. Ewing sarcoma cell lines in PMID 29672864, where PSPH baseline expression, protein and flux are high. NO primary infant KMT2A-rearranged sample and NO normal human pro-B cell.
cell stateMeasured in the drug-treated arresting state at day 7 of continuous menin-inhibitor exposure under uncontrolled medium serine supply - and it did not move, which is the entry's content. At day 2 the value is -0.14. The states in which PSPH loss has a human phenotype are PRENATAL AND POSTNATAL GROWTH and psychomotor development; an adult presentation with myeloneuropathy and limb contractures is also on record (PMID 26589312, verified bibliographically, not read).
epigenetic readoutH3K4me3 WAS NOT MEASURED AT PSPH. PMID 29672864 reports reduced H3K4me3 enrichment specifically at the PHGDH promoter, and names PSPH only among the SSP genes whose expression fell - so the chromatin measurement exists for one of the three enzymes and not for this one. That asymmetry in the source is worth recording because it matches the transcript asymmetry measured here: the gene with the chromatin measurement is the gene with the large menin-selective fall, and PSPH has neither. No H3K4me3, H3K79me2, KMT2A or menin ChIP at the PSPH locus exists in any system.
shown for fusionREADOUT ONLY, AND AS A NEGATIVE. PSPH's near-null (-0.48, margin -0.01) is measured in KMT2A::AFF1 (RS4;11, MV4;11) and KMT2A::MLLT3 (MOLM13). Its positive regulation by menin is shown only in Ewing sarcoma, which carries no KMT2A fusion. No mechanism, chromatin measurement or dependency has been shown for PSPH in any fusion.
the three enzyme pathway does not move as a unitPHGDH -3.24, PSAT1 -2.40, PSPH -0.48 in the same RS4;11 day-7 samples, all three detected. Any claim in this graph phrased as 'menin inhibition collapses the serine synthesis pathway' is wrong by 2.8 log2 for one of the pathway's three canonical members, and a single co-regulating transcription factor cannot produce that spread.
absence classmeasured-not-analysed
absence class noteThe near-null was in deposited data and unanalysed. The item that would sharpen this entry most is not an absence at all: the per-gene SSP magnitudes in PMID 29672864 are in a figure panel that was not opened.
mv411 independent lab
menin_vtp50469_500nM-0.640menin_vtp50469_500nM: -0.64margin-0.570margin: -0.57dot1l_sgc0946_5uM-0.060dot1l_sgc0946_5uM: -0.06dmso_baseline_log2cpm2.450dmso_baseline_log2cpm: 2.45
the measurement array gse63664 every probe
244819_x_at4.940244819_x_at: 4.94205048_s_at7.880205048_s_at: 7.88205194_at11.4205194_at: 11.37
the measurement rs411 d7 log2fc
{
  "vtp50469_330nM": -0.48,
  "epz5676_1uM": -0.47,
  "vtp_minus_epz": -0.01,
  "dmso_baseline_log2cpm": 5.72,
  "detected": true,
  "floor_collision": false,
  "d2_vtp": -0.144,
  "excluded_from_the_serine_arm_because": "|VTP| below the pre-declared 1.0 log2 threshold - and that exclusion is this entry's finding, not a technicality"
}
molm13 kmt2a mllt3
{
  "vtp": -0.306,
  "epz": -0.073,
  "dmso_baseline_log2cpm": 6.38,
  "detected": true
}
mv411 independent lab — the numbers behind the chart
{
  "menin_vtp50469_500nM": -0.64,
  "dot1l_sgc0946_5uM": -0.06,
  "margin": -0.57,
  "dmso_baseline_log2cpm": 2.45
}
the measurement array gse63664 every probe — the numbers behind the chart
{
  "205048_s_at": {
    "rs411_dmso_log2_rma": 7.88,
    "rs411_mi22": -0.51,
    "sem_dmso": 8.7,
    "sem_mi22": -0.47,
    "reh_dmso": 7.91,
    "reh_mi22": 0.48
  },
  "205194_at": {
    "rs411_dmso_log2_rma": 11.37,
    "rs411_mi22": -0.2,
    "sem_dmso": 11.65,
    "sem_mi22": -0.07,
    "reh_dmso": 11.42,
    "reh_mi22": 0.16
  },
  "244819_x_at": {
    "rs411_dmso_log2_rma": 4.94,
    "note": "BELOW the 6.0 log2 RMA floor in all three lines; not interpreted"
  }
}
essentiality
{
  "depmap_release": null,
  "depmap_release_note": "Rule 83: no release identifier in the Open Targets payload. Fetched 2026-09-22.",
  "depmap_screens": 1258,
  "depmap_tissue_blocks_flattened": 29,
  "chronos_mean": -0.1161,
  "chronos_median": -0.1071,
  "pct_lines_below_minus_0_5": 0.6,
  "leukaemia_screens": 57,
  "leukaemia_mean_gene_effect": -0.1249,
  "depmap_common_essential": "not asserted",
  "within_pathway_spread": "PHGDH 1.1%, PSAT1 8.2%, PSPH 0.6% - more than an order of magnitude across three steps of one pathway"
}
How this could bite us back
  • **Germline biallelic PSPH loss causes pre- AND postnatal growth retardation with psychomotor retardation.** Growth is the clinical priority immediately behind survival in an infant, and unlike PHGDH and PSAT1 the PSPH phenotype is explicitly a growth phenotype rather than a malformation one - which makes it the most directly relevant of the three to a child who survives treatment.
  • **PSPH sits upstream of D-serine**, an NMDA-receptor co-agonist, so the pathway's product is a neuromodulator as well as a building block. That is a CNS-toxicity mechanism for any serine-pathway inhibitor that is distinct from the growth and malformation phenotypes, and it applies to PHGDH and PSAT1 inhibition too.
  • **This entry is a negative result and should be cited as one.** Its value is that it stops the graph phrasing the serine collapse at pathway level; it does not nominate anything and there is no PSPH inhibitor.
Still open
  1. Do the per-gene SSP magnitudes in PMID 29672864 show PSPH moving as much as PHGDH in Ewing sarcoma? The abstract groups them and the figure was not opened. This is one panel and it decides whether this entry's central contrast between the two diseases is real.
  2. Does serine OUTPUT fall in KMT2A-rearranged cells under a menin inhibitor despite PSPH being unchanged? PHGDH's collapse shuts the pathway's entrance while PSPH's exit stays open. 13C-glucose tracing under VTP-50469 in RS4;11 is the measurement, it has been done in Ewing sarcoma, and it has never been done in this disease.
  3. Is PSPH in excess of requirement in these cells? If so its transcript is uninformative about flux and the near-null means nothing mechanistically - which would also explain its 0.6% DepMap fraction. An enzyme-activity measurement, not a transcript, settles it.
Every source behind this entry (4)
  1. E1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.dataset

    On a pre-registered panel PSPH does not reach the 1 log2 threshold in any line: RS4;11 day 7 VTP-50469 330 nM -0.48 and EPZ5676 -0.47 from a detected baseline of 5.72 log2 CPM (margin -0.01), day 2 -0.14, MOLM13 -0.31 from a detected baseline of 6.38, MV4;11 -0.64 from a baseline of 2.45; and on the GPL570 array probe 205048_s_at gives -0.51 in RS4;11 (baseline 7.88), -0.47 in SEM (8.70) and +0.48 in REH (7.91), probe 205194_at gives -0.20 (11.37), -0.07 (11.65) and +0.16 (11.42), and probe 244819_x_at is below the 6.0 log2 RMA floor in all three lines - while PHGDH and PSAT1 in the same samples fall 3.24 and 2.40 log2.

    What this evidence cannot show

    One line per platform, single doses, NO dose-response, n=2-3 per arm, day 7 of continuous exposure so arrest is a competing explanation. No series records the amino-acid composition of the medium, and this is an amino-acid-response panel. MI-2-2 in the array arm is the WEAK compound, so the REH wild-type contrast has little dynamic range. PSPH's RNA-seq baseline of 5.72 log2 CPM is the lowest of the three SSP enzymes, so a compression effect at lower expression cannot be excluded as a partial explanation - though 5.72 is well above the floor and the array's 11.37 log2 RMA probe, far from any ceiling or floor, gives the same near-null.

    Evidence that argues against this (1)
    • A near-null on the committed release step is not evidence that serine output is unchanged. PSPH may be in excess of requirement, in which case a large fall in PHGDH would reduce flux with no PSPH change at all, and the transcript comparison would be uninformative about the pathway. Only a 13C-glucose tracing measurement distinguishes these, and PMID 29672864 did exactly that in Ewing sarcoma and found flux abrogated. Svoboda LK et al. 2018
  2. E2established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

    PSPH DepMap gene effect is mean -0.1161, median -0.1071, with 0.6% of 1,258 screens below -0.5 and a leukaemia mean of -0.1249 over 57 screens, with all 29 tissue blocks flattened and approvedSymbol read back as PSPH.

    What this evidence cannot show

    Rule 83: the payload carries NO release identifier, so depmap_release is recorded as null and absolute values drift quarterly; the cross-gene contrast is the durable part. Leukaemia screens are matched on the payload's own diseaseFromSource string against four substrings and are NOT split by KMT2A status. Rule 84: no median-split proportion is reported - the percentage is against an absolute -0.5 threshold. A CRISPR knockout in nutrient-replete medium understates a biosynthetic dependency.

    Evidence that argues against this (1)
    • 0.6% of 1,258 lines is the second-lowest fraction among the three SSP enzymes and sits beside PSAT1's 8.2% - so within one three-step pathway the DepMap fractions span more than an order of magnitude, which argues the CRISPR screen is measuring something other than pathway requirement (most likely enzyme excess and step-specific flux control) and weakens every dependency statement in this beat. Possemato R et al. 2011
  3. E3established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

    UniProt reviewed human record P78330 (SERB_HUMAN) has primary gene name PSPH with no synonyms, length 225 aa, catalyses the last irreversible step in the biosynthesis of L-serine from carbohydrates by dephosphorylating O-phospho-L-serine, notes that the L-serine produced can be used in protein synthesis, to produce other amino acids, in nucleotide metabolism, in glutathione synthesis or be racemised to the neuromodulator D-serine, carries a single SUBCELLULAR LOCATION statement of Cytoplasm/cytosol with ECO:0000305 curator-inference support citing PubMed 1965857, and records phosphoserine phosphatase deficiency, an autosomal recessive disorder causing pre- and postnatal growth retardation, moderate psychomotor retardation and facial features suggestive of Williams syndrome.

    What this evidence cannot show

    Resolved 2026-09-22 with gene_exact:PSPH AND organism_id:9606 AND reviewed:true; exactly one reviewed row, gene_primary and length read back. Rule 91: the localisation is ECO:0000305 curator inference citing PubMed 1965857, a 1990 partial purification and characterisation of phosphoserine phosphatase from human BRAIN - a biochemical purification paper, not a localisation study - and its abstract was not read. Same shape as MTHFD1's record. The disease description is a curated summary; the founding mutation report is PMID 14673469 and an adult presentation with myeloneuropathy is PMID 26589312, both verified bibliographically and neither read.

    Evidence that argues against this (1)
    • The D-serine clause matters and cuts against any serine-pathway intervention in an infant: D-serine is an NMDA-receptor co-agonist and PSPH sits upstream of it, so the pathway's output is not only a building block but a neuromodulator. That is a mechanism for central nervous system toxicity distinct from the growth phenotype, and it applies to PHGDH and PSAT1 inhibition as well. Veiga-da-Cunha M et al. 2004
  4. E4strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    PMID 29672864 names PHGDH, PSAT1 and PSPH as the serine biosynthetic pathway genes whose baseline expression, protein and metabolic flux were confirmed high in Ewing sarcoma, and reports that inhibition of menin resulted in diminished expression of SSP genes together with reduced H3K4me3 at the PHGDH promoter and complete abrogation of de novo serine and glycine biosynthesis by 13C-glucose tracing; PubMed 2026-09-22 shows PSPH[tiab] returning 210 records of which exactly 1 is fusion-scoped and 1 menin-scoped, both being that same paper, and the UniProt-absent but commonly used short form PSP[tiab] returning 9,748 records with 2 fusion-scoped hits that were not opened.

    Menin regulates the serine biosynthetic pathway in Ewing sarcoma. · Svoboda LK, Teh SSK, Sud S, et al., Lawlor ER · J Pathol 2018
    PMID 29672864DOI
    What this evidence cannot show

    Abstract read this session; full text not retrieved, so the per-gene magnitudes of the SSP expression change in Ewing sarcoma were NOT seen - the abstract groups them. It is therefore possible that PSPH moved least in Ewing sarcoma too, which would make this entry's contrast between the two diseases smaller than stated. That is the single most important uncertainty in this entry and it is one figure panel away from being resolved. The system is Ewing sarcoma, which carries no KMT2A fusion. The alias PSP is not a UniProt synonym and collides heavily (progressive supranuclear palsy, pancreatic stone protein); its 2 fusion-scoped records were not read.

    Evidence that argues against this (1)
    • Because the Ewing abstract reports the three SSP genes as a group, this entry's headline contrast - 'all three fall in Ewing, only two in leukaemia' - rests on an abstract-level grouping and could be an artefact of how the abstract was written rather than a difference between diseases. Rule 80's point applies directly: the per-gene numbers are in a supporting figure that was not opened. Jimenez JA et al. 2021
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