Affinage

PAM

Peptidyl-glycine alpha-amidating monooxygenase · UniProt P19021

Round 2 corrected
Length
973 aa
Mass
108.3 kDa
Annotated
2026-04-29
130 papers in source corpus 19 papers cited in narrative 18 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PAM (peptidyl-glycine alpha-amidating monooxygenase) is a bifunctional, copper- and ascorbate-dependent type-1 integral membrane enzyme that catalyzes the two-step C-terminal amidation of secretory peptides: its PHM domain α-hydroxylates glycine-extended substrates, and its PAL domain cleaves the intermediate to yield amidated peptide and glyoxylate (PMID:8518727, PMID:26667899). Alternative splicing of the 27-exon gene generates soluble or membrane-anchored isoforms, and the intrinsically disordered cytosolic domain undergoes PKC-dependent phosphorylation at Ser937 to direct endosomal recycling rather than lysosomal degradation, while Uhmk1-mediated phosphorylation regulates nuclear import of an endoproteolytically released cytosolic fragment that activates gene expression retrogradely from secretory granules (PMID:8530412, PMID:20573687). PAM-dependent peptide amidation is essential for insect development, mammalian embryogenesis, and pancreatic β-cell insulin content; loss-of-function variants reduce amidating activity and are associated with type 2 diabetes risk and pituitary hypersecretion (PMID:10993678, PMID:30054598, PMID:37388215).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1990 Medium

    Cloning of human PAM cDNA and demonstration that a soluble truncated form retains full amidating activity established that the transmembrane domain is dispensable for catalysis, framing the protein as a modular enzyme.

    Evidence cDNA cloning from thyroid carcinoma library, heterologous expression in COS cells with enzyme activity assay

    PMID:2357221

    Open questions at the time
    • Single lab observation without independent replication at that time
    • Physiological relevance of soluble forms unclear
  2. 1992 High

    Genomic characterization revealed a 27-exon gene with extensive alternative splicing that generates soluble versus membrane-bound and monofunctional versus bifunctional isoforms, explaining the tissue-specific diversity of PAM products.

    Evidence Genomic cloning, exon mapping, and Southern blotting in rat; chromosomal mapping in human

    PMID:1448112

    Open questions at the time
    • Tissue-specific splicing regulation mechanisms undefined
    • Functional significance of each splice form not individually tested
  3. 1993 High

    Biochemical reconstitution defined the two-step reaction — PHM-catalyzed copper/ascorbate-dependent α-hydroxylation followed by PAL-catalyzed lyase cleavage — and showed that the PAL domain allosterically modulates PHM kinetics within the bifunctional protein.

    Evidence Protein purification, limited endoproteolysis, N-terminal sequencing, and enzyme kinetics in HEK-293 cells

    PMID:8486658 PMID:8518727

    Open questions at the time
    • No atomic-resolution structure at this stage
    • In vivo relevance of intramolecular domain modulation not tested
  4. 1995 High

    Identification of PKC-dependent phosphorylation at Ser937 as a trafficking switch — preventing lysosomal mis-sorting after endocytosis — established that the cytosolic domain actively controls PAM's itinerary through the endosomal system.

    Evidence Metabolic 32P labeling, Ser937→Ala mutagenesis, antibody internalization assay in AtT-20 and HEK-293 cells

    PMID:8530412

    Open questions at the time
    • Identity of the phosphatase reversing Ser937 phosphorylation unknown
    • Kinase specificity beyond PKC not explored
  5. 1997 High

    Discovery that the PAM cytosolic domain binds Kalirin, a Rac1-specific GEF, linked luminal enzymatic processing to cytoskeletal remodeling and neurite morphogenesis, revealing a signaling role beyond peptide amidation.

    Evidence Yeast two-hybrid, GST pull-down, co-expression in AtT-20 cells with neurite morphology readout

    PMID:9139723

    Open questions at the time
    • Whether Kalirin interaction is direct or scaffolded in vivo not settled
    • Rac1-dependent downstream effectors not mapped
  6. 1998 Medium

    Identification of P-CIP1 as a second cytosolic-domain interactor localized to recycling endosomes extended the model that PAM's cytoplasmic tail coordinates vesicular trafficking.

    Evidence Yeast two-hybrid, pull-down, immunofluorescence colocalization with endosomal markers

    PMID:9837933

    Open questions at the time
    • No direct rescue experiment to confirm functional role of P-CIP1 in PAM recycling
    • Endogenous stoichiometry of P-CIP1–PAM complex not determined
  7. 2000 High

    Genetic ablation of the Drosophila PHM ortholog proved that PHM-dependent amidation is essential for organism-level viability, with null mutants failing to complete developmental molting transitions.

    Evidence PHM null mutants, neuropeptide immunostaining, transgenic rescue in Drosophila

    PMID:10993678

    Open questions at the time
    • Specific amidated peptide substrates driving lethality not identified
    • Mammalian in vivo essentiality confirmed later but not here
  8. 2010 High

    The demonstration that endoproteolytic release of PAM's cytosolic domain allows nuclear translocation and gene regulation (e.g., Aqp1), modulated by Uhmk1 phosphorylation and confirmed in PAM heterozygous mice, established a retrograde secretory-granule-to-nucleus signaling pathway.

    Evidence Subcellular fractionation, phosphomimetic mutagenesis, microarray, PAM heterozygous mouse model

    PMID:20573687

    Open questions at the time
    • Full repertoire of nuclear gene targets unknown
    • Mechanism of PAM-CD-dependent transcriptional activation unclear
  9. 2015 High

    Crystal structures of both PHM and PAL catalytic cores resolved metal coordination and substrate-binding geometry; phylogenetic surveys extending to Chlamydomonas and cilia indicated PAM's evolutionary antiquity and roles beyond neuropeptide processing.

    Evidence X-ray crystallography, enzymatic assays, knockout mouse (mid-gestation lethal), phylogenetic analysis

    PMID:26667899

    Open questions at the time
    • Ciliary function of PAM mechanistically uncharacterized
    • How PAM contributes to copper homeostasis remains unclear
  10. 2018 High

    Functional validation of PAM missense variants (p.Asp563Gly, p.Ser539Trp) linked reduced amidating activity to lower β-cell insulin content and type 2 diabetes risk, directly connecting PAM enzymology to metabolic disease.

    Evidence Variant activity assays, EndoC-βH1 human β-cell model, primary human islets, insulin secretion measurements

    PMID:24464100 PMID:30054598

    Open questions at the time
    • Which specific amidated peptides in β-cells are functionally critical remains undefined
    • Heterozygous loss-of-function penetrance and modifier genes not characterized
  11. 2023 High

    Enrichment of germline loss-of-function PAM variants in pituitary hypersecretion patients, validated by splicing and activity assays, expanded PAM's disease spectrum beyond diabetes to neuroendocrine tumor predisposition.

    Evidence Germline sequencing, minigene splicing assay, amidation activity assay, UK Biobank exome association

    PMID:37388215

    Open questions at the time
    • Mechanism linking reduced amidation to pituitary hyperplasia/hypersecretion not delineated
    • Whether somatic second hits contribute to tumorigenesis unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the identities of the specific amidated substrates driving β-cell and pituitary phenotypes, the molecular mechanism of PAM's ciliary function, and how the retrograde nuclear signaling pathway converges on transcription.
  • Critical amidated substrates in β-cells and pituitary not identified
  • PAM ciliary function mechanistically undefined
  • Transcription factor partners of nuclear PAM-CD unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 6 GO:0016829 lyase activity 3 GO:0140096 catalytic activity, acting on a protein 2
Localization
GO:0031410 cytoplasmic vesicle 4 GO:0005886 plasma membrane 3 GO:0005768 endosome 2 GO:0005634 nucleus 1 GO:0005929 cilium 1
Pathway
R-HSA-392499 Metabolism of proteins 4 R-HSA-9609507 Protein localization 3 R-HSA-162582 Signal Transduction 2 R-HSA-1643685 Disease 2 R-HSA-1266738 Developmental Biology 1
Partners
KALRNPCIP1UHMK1

Evidence

Reading pass · 18 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1990 Human PAM (peptidylglycine α-amidating monooxygenase) cDNA was cloned from a thyroid carcinoma library. A truncated form lacking the C-terminal transmembrane domain was functionally expressed in COS cells, producing a soluble, active enzyme with a 20-fold increase in amidating activity over controls, establishing that the transmembrane domain is dispensable for catalytic activity. cDNA cloning, heterologous expression in COS cells, enzyme activity assay Biochemical and biophysical research communications Medium 2357221
1992 The rat PAM gene consists of 27 exons spanning >160 kb. Alternative splicing within the PHM region generates soluble monofunctional PHM proteins; alternative splicing at the transmembrane domain exon generates integral membrane or soluble bifunctional PAM proteins; and a single alternatively spliced exon between PHM and PAL domains permits endoproteolytic separation of the two catalytic activities. The human PAM gene was mapped to chromosome 5q. Genomic cloning, Southern blotting, exon mapping, hybrid cell panel analysis Molecular endocrinology High 1448112
1993 PAM is a multifunctional type-1 integral membrane protein containing two sequential catalytic domains: peptidylglycine α-hydroxylating monooxygenase (PHM), which performs copper- and ascorbate-dependent α-hydroxylation of peptidylglycine substrates, and peptidyl-α-hydroxyglycine α-amidating lyase (PAL), which cleaves the N–C bond to produce amidated peptide and glyoxylate. Tissue-specific alternative splicing generates integral membrane or soluble forms, and the cytosolic C-terminal domain contains routing information for retrieval from the cell surface. Protein purification, enzyme assays, alternative splicing analysis, transfected cell expression Protein science High 8518727
1993 Endoproteolytic removal of the C-terminal region from bifunctional soluble PAM-3 (PHM+PAL) shifted the PHM pH optimum to more alkaline, increased PHM kcat, and decreased its Km for peptidylglycine substrate, while PAL activity was unaffected. This demonstrated that the PAL domain and C-terminal region modulate PHM catalytic properties within the bifunctional protein. Protein purification from transfected HEK-293 cells, limited endoproteolysis, N-terminal sequencing, enzyme kinetics The Journal of biological chemistry High 8486658
1995 The cytosolic domain of integral membrane PAM is phosphorylated on Ser932 and Ser937 by protein kinase C (PKC). Phosphorylation at Ser937 is required for correct post-endocytic routing of PAM: a Ser937→Ala mutant is abnormally targeted to lysosomes upon internalization rather than being recycled, establishing a role for PKC-mediated phosphorylation in PAM trafficking. Metabolic [32P] labeling, truncation mutagenesis, site-directed mutagenesis (Ser937→Ala), subcellular fractionation, PAM antibody internalization assay in AtT-20 and HEK-293 cells The Journal of biological chemistry High 8530412
1997 Using yeast two-hybrid screening, the cytosolic routing domain of PAM was found to interact with P-CIP10 (later named Kalirin), a 217-kDa cytosolic protein containing nine spectrin-like repeats and Dbl homology/pleckstrin homology domains typical of GDP/GTP exchange factors. Kalirin binds Rac1 but not RhoA or Cdc42, and co-expression with PAM in corticotrope tumor cells accelerates PAM turnover and promotes longer, more branched neuritic processes, suggesting Kalirin links PAM lumenal activity to cytoskeletal regulation. Yeast two-hybrid, GST pull-down, co-expression in AtT-20 cells, neurite morphology assay, GTPase binding assay The Journal of biological chemistry High 9139723
1998 P-CIP1, a novel 435-amino-acid cytosolic protein identified by yeast two-hybrid as a PAM cytosolic domain interactor, associates specifically with wild-type PAM-1 but not with trafficking-defective PAM-1 mutants. P-CIP1 localizes to recycling endosomes (overlapping with secretory carrier membrane proteins, transferrin, and Rab11), suggesting it regulates PAM trafficking through the endosomal pathway. Yeast two-hybrid, in vitro pull-down, co-expression in endocrine and fibroblast cells, immunofluorescence colocalization with endosomal markers The Journal of biological chemistry Medium 9837933
2000 In Drosophila, PHM (the α-hydroxylating monooxygenase domain/activity of PAM) is the rate-limiting enzyme for C-terminal α-amidation of neuropeptides. PHM null mutants lack amidated peptides but retain non-amidated neuropeptide precursors and other biosynthetic enzymes. PHM mutants display phenotypes resembling ecdysone-response gene mutations, including failure to molt and pupal lethality, establishing that PHM-dependent peptide amidation is essential for developmental transitions between stages. Genetic null mutants, enzyme activity assay, neuropeptide immunostaining, transgenic rescue with inducible PHM transgene Developmental biology High 10993678
2003 Pam (PAM/MYCBP2) was found to associate with the tuberin–hamartin (TSC2–TSC1) complex in rat brain. The C-terminus of Pam containing the RING zinc finger domain binds directly to tuberin. In cortical neurons, Pam co-localizes with tuberin and hamartin in neurites and growth cones. Genetic studies in Drosophila showed that the Pam ortholog Highwire (HIW) can negetically interact with the Tsc1·Tsc2 complex, consistent with PAM acting as a potential E3 ubiquitin ligase that regulates TSC1/TSC2 complex stability. Co-immunoprecipitation from rat brain, yeast two-hybrid domain mapping, immunofluorescence colocalization in cortical neurons, Drosophila genetic epistasis The Journal of biological chemistry Medium 14559897
2004 PAM (Protein Associated with Myc/MYCBP2) is localized to the endoplasmic reticulum in HeLa cells. Treatment with sphingosine-1-phosphate (S1P), purified from serum, induces translocation of PAM to the plasma membrane within 15 min, persisting up to 120 min. This PAM translocation mediates a late phase (20–240 min) of adenylyl cyclase inhibition that is PAM-dependent, distinct from an early Gi-mediated phase. Thus PAM acts as the longest-lasting non-transcriptional inhibitor of adenylyl cyclase activity known, enabling sustained inhibition of cAMP signaling. Subcellular fractionation, immunofluorescence microscopy, adenylyl cyclase activity assay, S1P purification, siRNA knockdown The EMBO journal High 15257286
2008 The RCC1 (Regulator of Chromatin Condensation) domain of PAM (MYCBP2) was identified as a binding partner of the K+/Cl− cotransporter KCC2 via yeast two-hybrid screening. The RCC1 domain of PAM binds to a 20-amino-acid region on the KCC2 C-terminus, as confirmed by GST pull-down and co-immunoprecipitation in HEK293 cells. Co-expression of RCC1/PAM with KCC2 increases KCC2-mediated 86Rb+/K+ flux, and a point mutant in the KCC2 binding region abolishes both PAM interaction and N-ethylmaleimide activation of KCC2, establishing PAM as a positive modulator of KCC2 cotransporter function. Yeast two-hybrid, GST pull-down, co-immunoprecipitation in HEK293, 86Rb+/K+ uptake assay, site-directed mutagenesis Cellular physiology and biochemistry High 18769030
2010 E3 ligases Arf-bp1 and Pam (MYCBP2) co-purify with the circadian heme receptor Rev-erbα and are required for its ubiquitination and proteasomal degradation. RNAi-mediated depletion of Arf-bp1 or Pam stabilizes Rev-erbα protein and protects it from degradation triggered by lithium (a GSK3β inhibitor) or serum shock. This degradation pathway controls expression of Rev-erbα-regulated clock genes including Bmal1 and modulates circadian function in mouse hepatoma cells. Affinity purification/co-IP, ubiquitination assay, RNAi knockdown, cycloheximide chase, circadian gene expression analysis Proceedings of the National Academy of Sciences of the United States of America High 20534529
2010 The cytosolic domain (CD) of PAM (amidating monooxygenase) is phosphorylated by U2AF homology motif kinase 1 (Uhmk1/J83). Uhmk1 is concentrated in the nucleus but cycles rapidly between nucleus and cytosol. Endoproteolytic cleavage of integral membrane PAM releases a soluble CD fragment that localizes to the nucleus. Phosphomimetic mutations in PAM-CD or overexpression of active Uhmk1 reduces nuclear localization of PAM-CD. Nuclear PAM-CD increases expression of a subset of genes including aquaporin 1 (Aqp1); this relationship is confirmed in vivo in PAM heterozygous mice. Thus, a retrograde signaling pathway exists from secretory granules to the nucleus via PAM-CD cleavage. Subcellular fractionation, phosphomimetic mutagenesis, Uhmk1 overexpression/knockdown, microarray gene expression analysis, in vivo PAM heterozygous mouse model Molecular endocrinology High 20573687
2015 PAM (amidating monooxygenase) is an evolutionarily ancient bifunctional enzyme: the PHM domain uses copper, ascorbate (vitamin C), and molecular oxygen to hydroxylate the Cα of C-terminal glycine-extended peptide substrates; the PAL domain then cleaves the N–Cα bond to yield amidated product and glyoxylate. Crystal structures of both catalytic cores have been determined, revealing metal-coordination and substrate-binding mechanisms. PAM is also found in cilia and in Chlamydomonas (a unicellular eukaryote), indicating a role beyond peptide processing. The cytosolic domain, though intrinsically disordered, is essential for PAM trafficking. Evidence also supports a role for PAM in copper homeostasis and in retrograde signaling from the secretory pathway lumen to the nucleus. Crystal structure determination, enzymatic assays, knockout mouse model (lethal at mid-gestation), phylogenetic survey, cellular localization studies Journal of molecular endocrinology High 26667899
2016 Neuronal differentiation increases copper demand within the secretory pathway. This is facilitated in part by upregulation of the copper transporter ATP7A and its chaperone Atox1. PAM (peptidylglycine α-amidating monooxygenase), a copper-dependent enzyme in the secretory pathway, is among the copper-dependent enzymes whose expression is elevated in differentiated neurons, directly linking copper availability to PAM-dependent amidation capacity. Quantitative real-time imaging of copper/glutathione redox state, qPCR, western blotting in differentiating neuronal cells Nature communications Medium 26879543
2018 PAM (MYCBP2) forms a noncanonical SCF-like ubiquitin ligase complex containing FBXO45 and SKP1 but lacking CUL1. FBXO45 is required for assembly of the PAM/FBXO45/SKP1 complex, not merely for substrate recognition. SKP1 acts as an auxiliary component of the substrate recognition module, enhancing FBXO45 binding to NMNAT2. PAM polyubiquitinates NMNAT2 and promotes its proteasomal degradation, establishing the biochemical mechanism by which PAM/PHR proteins regulate axon degeneration through NMNAT2. Affinity purification/co-immunoprecipitation, in vitro ubiquitination assay, proteasome inhibitor treatment, cycloheximide chase, domain-specific interaction mapping in C. elegans and human cells The Journal of biological chemistry High 29997255
2018 Missense variants in PAM (amidating monooxygenase) — p.Asp563Gly and p.Ser539Trp — are associated with type 2 diabetes risk and impact negatively on overall PAM amidating activity via defects in protein expression and catalytic function. PAM deficiency in a human β-cell model and primary cadaveric islets reduces insulin content and alters dynamics of insulin secretion, establishing a direct role for PAM-mediated peptide amidation in β-cell function. Functional variant analysis (Western blot, amidation activity assay in cell lysates and serum), human β-cell model (EndoC-βH1), primary human islets, insulin secretion assay Nature genetics High 24464100 30054598
2023 Germline loss-of-function variants in PAM (amidating monooxygenase) are enriched in individuals with pituitary hypersecretion (including growth hormone excess and Cushing disease). Seven heterozygous likely pathogenic SNVs were identified and functionally validated: in vitro assays showed reduced protein expression, abnormal splicing (minigene assay), and decreased amidating activity in cell lysates and patient serum, confirming deleterious effects on PAM function and linking PAM to pituitary tumor/hypersecretion pathogenesis. Germline sequencing, CNV analysis, Western blotting, minigene splicing assay, amidation activity assay in cell lysates and serum, UK Biobank exome analysis Frontiers in endocrinology High 37388215

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Cell 2861 17081983
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2009 Common variants conferring risk of schizophrenia. Nature 1320 19571808
2015 Engineered CRISPR-Cas9 nucleases with altered PAM specificities. Nature 1268 26098369
2018 Evolved Cas9 variants with broad PAM compatibility and high DNA specificity. Nature 1152 29512652
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2014 Structural basis of PAM-dependent target DNA recognition by the Cas9 endonuclease. Nature 975 25079318
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
2017 Engineered Cpf1 variants with altered PAM specificities. Nature biotechnology 324 28581492
2016 Identifying and Visualizing Functional PAM Diversity across CRISPR-Cas Systems. Molecular cell 251 27041224
2009 Proteomic analysis of human parotid gland exosomes by multidimensional protein identification technology (MudPIT). Journal of proteome research 237 19199708
2014 Identification of low-frequency and rare sequence variants associated with elevated or reduced risk of type 2 diabetes. Nature genetics 231 24464100
2010 Poor replication of candidate genes for major depressive disorder using genome-wide association data. Molecular psychiatry 220 20351714
2016 PAM-Dependent Target DNA Recognition and Cleavage by C2c1 CRISPR-Cas Endonuclease. Cell 208 27984729
1993 Peptidylglycine alpha-amidating monooxygenase: a multifunctional protein with catalytic, processing, and routing domains. Protein science : a publication of the Protein Society 206 8518727
2021 CRISPR technologies and the search for the PAM-free nuclease. Nature communications 205 33483498
1993 PAM, a novel plasminogen-binding protein from Streptococcus pyogenes. The Journal of biological chemistry 184 8244975
2018 PAM identification by CRISPR-Cas effector complexes: diversified mechanisms and structures. RNA biology 178 30109815
2004 Oxidative stress-induced apoptosis is associated with alterations in mitochondrial caspase activity and Bcl-2-dependent alterations in mitochondrial pH (pHm). Brain research bulletin 165 15036564
2005 Scanning the human proteome for calmodulin-binding proteins. Proceedings of the National Academy of Sciences of the United States of America 139 15840729
2013 In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in urine. Proteomics 138 23533145
2008 Phenylalanine ammonia-lyase (PAL) and cinnamate 4-hydroxylase (C4H) and catechins (flavan-3-ols) accumulation in tea. Functional & integrative genomics 133 18679731
2013 Proteomic analysis of podocyte exosome-enriched fraction from normal human urine. Journal of proteomics 126 23376485
2016 Deciphering, Communicating, and Engineering the CRISPR PAM. Journal of molecular biology 125 27916599
2017 Photo-affinity labeling (PAL) in chemical proteomics: a handy tool to investigate protein-protein interactions (PPIs). Proteome science 122 28652856
2016 Structural Basis for the Altered PAM Specificities of Engineered CRISPR-Cas9. Molecular cell 118 26990991
1997 Kalirin, a cytosolic protein with spectrin-like and GDP/GTP exchange factor-like domains that interacts with peptidylglycine alpha-amidating monooxygenase, an integral membrane peptide-processing enzyme. The Journal of biological chemistry 113 9139723
1990 Expression and modulation of nerve growth factor in murine keratinocytes (PAM 212). The Journal of clinical investigation 110 2318966
2010 Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score. Molecular medicine (Cambridge, Mass.) 108 20379614
2020 An engineered ScCas9 with broad PAM range and high specificity and activity. Nature biotechnology 103 32393822
2020 The multifarious roles of Tol-Pal in Gram-negative bacteria. FEMS microbiology reviews 97 32472934
2016 Neuronal differentiation is associated with a redox-regulated increase of copper flow to the secretory pathway. Nature communications 96 26879543
2020 A Cas9 with PAM recognition for adenine dinucleotides. Nature communications 91 32424114
2019 Genome Engineering in Rice Using Cas9 Variants that Recognize NG PAM Sequences. Molecular plant 88 30928636
2010 E3 ligases Arf-bp1 and Pam mediate lithium-stimulated degradation of the circadian heme receptor Rev-erb alpha. Proceedings of the National Academy of Sciences of the United States of America 86 20534529
1985 Coding sequences for vasoactive intestinal peptide and PHM-27 peptide are located on two adjacent exons in the human genome. Proceedings of the National Academy of Sciences of the United States of America 82 2987932
2018 Cas4 Nucleases Define the PAM, Length, and Orientation of DNA Fragments Integrated at CRISPR Loci. Molecular cell 80 29883605
2021 Engineered prime editors with PAM flexibility. Molecular therapy : the journal of the American Society of Gene Therapy 79 33636398
2017 Structural Basis for the Altered PAM Recognition by Engineered CRISPR-Cpf1. Molecular cell 78 28595896
1999 In vitro characterization of peptidoglycan-associated lipoprotein (PAL)-peptidoglycan and PAL-TolB interactions. Journal of bacteriology 77 10515919
2000 PHM is required for normal developmental transitions and for biosynthesis of secretory peptides in Drosophila. Developmental biology 74 10993678
2015 60 YEARS OF POMC: From POMC and α-MSH to PAM, molecular oxygen, copper, and vitamin C. Journal of molecular endocrinology 71 26667899
2003 Pam and its ortholog highwire interact with and may negatively regulate the TSC1.TSC2 complex. The Journal of biological chemistry 69 14559897
2018 Type 2 diabetes risk alleles in PAM impact insulin release from human pancreatic β-cells. Nature genetics 66 30054598
2012 The phenylalanine ammonia lyase (PAL) gene family shows a gymnosperm-specific lineage. BMC genomics 66 22759610
2017 A Role for Mitochondrial Translation in Promotion of Viability in K-Ras Mutant Cells. Cell reports 64 28700943
2018 Phenylalanine ammonia lyase (PAL): From discovery to enzyme substitution therapy for phenylketonuria. Molecular genetics and metabolism 62 29941359
1998 Molecular co-operation between protein PAM and streptokinase for plasmin acquisition by Streptococcus pyogenes. The Journal of biological chemistry 62 9497374
1990 Human peptidylglycine alpha-amidating monooxygenase: cDNA, cloning and functional expression of a truncated form in COS cells. Biochemical and biophysical research communications 60 2357221
1986 The receptors of the VIP family peptides (VIP, secretin, GRF, PHI, PHM, GIP, glucagon and oxyntomodulin). Specificities and identity. Peptides 60 3018707
2018 Estrogen-regulated feedback loop limits the efficacy of estrogen receptor-targeted breast cancer therapy. Proceedings of the National Academy of Sciences of the United States of America 59 29987050
2020 High-Throughput Screens of PAM-Flexible Cas9 Variants for Gene Knockout and Transcriptional Modulation. Cell reports 54 32130891
1984 Cyclic AMP regulation of pro-vasoactive intestinal polypeptide/PHM-27 synthesis in human neuroblastoma cells. The Journal of biological chemistry 54 6086627
2018 PAM-Antagonists: A Better Way to Block Pathological Receptor Signaling? Trends in pharmacological sciences 53 29885909
1996 A "double adaptor" method for improved shotgun library construction. Analytical biochemistry 53 8619474
1992 The multifunctional peptidylglycine alpha-amidating monooxygenase gene: exon/intron organization of catalytic, processing, and routing domains. Molecular endocrinology (Baltimore, Md.) 52 1448112
2023 PAM-flexible genome editing with an engineered chimeric Cas9. Nature communications 49 37794046
2018 Safety Studies of Pneumococcal Endolysins Cpl-1 and Pal. Viruses 48 30445722
2004 PAM mediates sustained inhibition of cAMP signaling by sphingosine-1-phosphate. The EMBO journal 47 15257286
2022 NUDT21 limits CD19 levels through alternative mRNA polyadenylation in B cell acute lymphoblastic leukemia. Nature immunology 46 36138187
2013 Genetic determinants of PAM-dependent DNA targeting and pre-crRNA processing in Sulfolobus islandicus. RNA biology 46 23392249
1986 Effects of VIP, PHM and substance P on blood vessels and secretory elements of the human submandibular gland. Regulatory peptides 46 2422707
1997 Large-scale concatenation cDNA sequencing. Genome research 45 9110174
1993 Use of endoproteases to identify catalytic domains, linker regions, and functional interactions in soluble peptidylglycine alpha-amidating monooxygenase. The Journal of biological chemistry 45 8486658
2012 Characterization, high-resolution mapping and differential expression of three homologous PAL genes in Coffea canephora Pierre (Rubiaceae). Planta 42 22349733
2021 PAL-mediated SA biosynthesis pathway contributes to nematode resistance in wheat. The Plant journal : for cell and molecular biology 41 33974322
2020 Simulated Microgravity Influences VEGF, MAPK, and PAM Signaling in Prostate Cancer Cells. International journal of molecular sciences 41 32070055
2019 Expression patterns of two pal genes of Pleurotus ostreatus across developmental stages and under heat stress. BMC microbiology 41 31655558
2018 PAM forms an atypical SCF ubiquitin ligase complex that ubiquitinates and degrades NMNAT2. The Journal of biological chemistry 41 29997255
2012 Phenylalanine ammonia lyase (PAL) enzyme activity and antioxidant properties of some cyanobacteria isolates. Food chemistry 41 23017408
2015 Characterisation of the willow phenylalanine ammonia-lyase (PAL) gene family reveals expression differences compared with poplar. Phytochemistry 40 26070140
2015 Structure and function of the Escherichia coli Tol-Pal stator protein TolR. The Journal of biological chemistry 40 26354441
2021 Scalable characterization of the PAM requirements of CRISPR-Cas enzymes using HT-PAMDA. Nature protocols 38 33547443
2010 Signaling from the secretory granule to the nucleus: Uhmk1 and PAM. Molecular endocrinology (Baltimore, Md.) 38 20573687
2022 Genome editing in animals with minimal PAM CRISPR-Cas9 enzymes. Nature communications 37 35552388
2020 Characterization of Cas12a nucleases reveals diverse PAM profiles between closely-related orthologs. Nucleic acids research 37 32329776
2019 Cas4-Cas1 fusions drive efficient PAM selection and control CRISPR adaptation. Nucleic acids research 37 30937444
2000 Morphology and DNA content analysis in the evaluation of first trimester placentas for partial hydatidiform mole (PHM). Human pathology 37 10987251
2019 DNA vaccine encoding OmpA and Pal from Acinetobacter baumannii efficiently protects mice against pulmonary infection. Molecular biology reports 36 31342294
2025 Custom CRISPR-Cas9 PAM variants via scalable engineering and machine learning. Nature 34 40262634
2019 Structural basis for the promiscuous PAM recognition by Corynebacterium diphtheriae Cas9. Nature communications 34 31036811
1995 Phosphorylation of the cytosolic domain of peptidylglycine alpha-amidating monooxygenase. The Journal of biological chemistry 33 8530412
2022 Phylogenomic analysis of phenylalanine ammonia-lyase (PAL) multigene family and their differential expression analysis in wheat (Triticum aestivum L.) suggested their roles during different stress responses. Frontiers in plant science 32 36247561
2021 Efficient and high-fidelity base editor with expanded PAM compatibility for cytidine dinucleotide. Science China. Life sciences 32 33420918
2013 QUIRKY interacts with STRUBBELIG and PAL OF QUIRKY to regulate cell growth anisotropy during Arabidopsis gynoecium development. Development (Cambridge, England) 32 24173806
1990 Monoclonal antibody PAL-M1 recognizes the transferrin receptor and is a progression marker in melanocytic lesions. The Journal of investigative dermatology 32 2366002
1984 Production of VIP- and PHM (human PHI)-related peptides in human neuroblastoma cells. Peptides 32 6548020
2023 Molecular basis and engineering of miniature Cas12f with C-rich PAM specificity. Nature chemical biology 30 37697004
2010 Design and synthesis of an orally active metabotropic glutamate receptor subtype-2 (mGluR2) positive allosteric modulator (PAM) that decreases cocaine self-administration in rats. Journal of medicinal chemistry 30 21155570
1998 P-CIP1, a novel protein that interacts with the cytosolic domain of peptidylglycine alpha-amidating monooxygenase, is associated with endosomes. The Journal of biological chemistry 30 9837933
1988 Complete nucleotide sequence of human vasoactive intestinal peptide/PHM-27 gene and its inducible promoter. Annals of the New York Academy of Sciences 29 2839091
2022 PCDetection: PolyA-CRISPR/Cas12a-based miRNA detection without PAM restriction. Biosensors & bioelectronics 27 35797934
2021 Cas12a variants designed for lower genome-wide off-target effect through stringent PAM recognition. Molecular therapy : the journal of the American Society of Gene Therapy 27 34687846
2021 Engineering a PAM-flexible SpdCas9 variant as a universal gene repressor. Nature communications 26 34824292
1985 Evidence for common precursors but differential processing of VIP and PHM in VIP-producing tumors. Peptides 26 3840886
2022 Roles of the Tol/Pal System in Bacterial Pathogenesis and Its Application to Antibacterial Therapy. Vaccines 25 35335056
2022 Genome-wide studies of PAL genes in sorghum and their responses to aphid infestation. Scientific reports 25 36581623
2024 PAM-flexible Engineered FnCas9 variants for robust and ultra-precise genome editing and diagnostics. Nature communications 24 38942756
2023 Genome-wide identification and expression analysis of phenylalanine ammonia-lyase (PAL) family in rapeseed (Brassica napus L.). BMC plant biology 24 37814209
2017 Methods for decoding Cas9 protospacer adjacent motif (PAM) sequences: A brief overview. Methods (San Diego, Calif.) 24 28344037
2016 The Pal pathway required for ambient pH adaptation regulates growth, conidiation, and osmotolerance of Beauveria bassiana in a pH-dependent manner. Applied microbiology and biotechnology 24 26754817
2022 Force-Generation by the Trans-Envelope Tol-Pal System. Frontiers in microbiology 23 35308353
2021 Compact SchCas9 Recognizes the Simple NNGR PAM. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 23 34874112
2020 Programming PAM antennae for efficient CRISPR-Cas9 DNA editing. Science advances 23 32494703
2022 A new family of CRISPR-type V nucleases with C-rich PAM recognition. EMBO reports 22 36268581
2021 Engineered dual selection for directed evolution of SpCas9 PAM specificity. Nature communications 21 33441553
2002 Developmental expression of PAM (protein associated with MYC) in the rodent brain. Brain research. Developmental brain research 21 12036515
2020 Quantification of the affinities of CRISPR-Cas9 nucleases for cognate protospacer adjacent motif (PAM) sequences. The Journal of biological chemistry 20 32241913
2019 Molecular basis for the PAM expansion and fidelity enhancement of an evolved Cas9 nuclease. PLoS biology 20 31603896
1991 Introduction of Tn916 and pAM beta 1 into Streptococcus bovis JB1 by conjugation. Applied and environmental microbiology 19 1662940
2022 Molecular Mechanism of D1135E-Induced Discriminated CRISPR-Cas9 PAM Recognition. Journal of chemical information and modeling 18 35666156
2010 The PAM-1 aminopeptidase regulates centrosome positioning to ensure anterior-posterior axis specification in one-cell C. elegans embryos. Developmental biology 17 20599902
2002 Enhanced expression of neuron-specific enolase (NSE) in pyothorax-associated lymphoma (PAL). Japanese journal of cancer research : Gann 17 11985791
1994 Location of PHM/VIP mRNA in human gastrointestinal tract detected by in situ hybridization. Cell and tissue research 17 8020060
2017 Discovery of a novel 2,4-dimethylquinoline-6-carboxamide M4 positive allosteric modulator (PAM) chemotype via scaffold hopping. Bioorganic & medicinal chemistry letters 16 29037946
2023 Completely Free from PAM Limitations: Asymmetric RPA with CRISPR/Cas12a for Nucleic Acid Assays. ACS sensors 15 38010352
2022 Expanding the Scope of Bacterial CRISPR Activation with PAM-Flexible dCas9 Variants. ACS synthetic biology 15 36378874
2021 Biochemical Characterization and Differential Expression of PAL Genes Associated With "Translocated" Peach/Plum Graft-Incompatibility. Frontiers in plant science 15 33679835
2019 Identification and immunological evaluation of novel TLR2 agonists through structure optimization of Pam3CSK4. Bioorganic & medicinal chemistry 15 31101493
2008 The RCC1 domain of protein associated with Myc (PAM) interacts with and regulates KCC2. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 15 18769030
2004 PAM-1, a natural human IgM antibody as new tool for detection of breast and prostate precursors. Human antibodies 15 15719499
2024 TracrRNA reprogramming enables direct PAM-independent detection of RNA with diverse DNA-targeting Cas12 nucleases. Nature communications 14 39003282
1996 Vascular effects and cyclic AMP production produced by VIP, PHM, PHV, PACAP-27, PACAP-38, and NPY on rabbit ovarian artery. Peptides 14 8844771
2023 Germline loss-of-function PAM variants are enriched in subjects with pituitary hypersecretion. Frontiers in endocrinology 13 37388215
2023 Expression profiling of the phenylalanine ammonia-lyase (PAL) gene family in ginkgo biloba L. Plant signaling & behavior 13 37903458
2019 Improving Editing Efficiency for the Sequences with NGH PAM Using xCas9-Derived Base Editors. Molecular therapy. Nucleic acids 13 31400605