Supplementary figure S1: Chemical structures of some examples of earlier characterized antibiotic and anticancer specialized metabolites: (A) salinilactam, (B) lactocillin, (C) streptochlorin, (D) abyssomicin C and (E) salinosporamide K. Figure S2. Heat map representing hierarchical classification of the SMGCs detected in all the metagenomes in the dataset. Table S1: The sampling locations of each of the sites in the dataset. Sample Sample Bio-project Site depth accession accession Samples Latitude Longitude Site description (m) number in SRA number in SRA AT0050m01B1-4C1 SRS598124 PRJNA193416 Atlantis II water column 50, 200, Water column AT0200m01C1-4D1 SRS598125 21°36'19.0" 38°12'09.0 700 and above the brine N "E (ATII 50, ATII 200, 1500 pool water layers AT0700m01C1-3D1 SRS598128 ATII 700, ATII 1500) AT1500m01B1-3C1 SRS598129 ATBRUCL SRS1029632 PRJNA193416 Atlantis II brine 21°36'19.0" 38°12'09.0 1996– Brine pool water ATBRLCL1-3 SRS1029579 (ATII UCL, ATII INF, N "E 2025 layers ATII LCL) ATBRINP SRS481323 PRJNA219363 ATIID-1a SRS1120041 PRJNA299097 ATIID-1b SRS1120130 ATIID-2 SRS1120133 2168 + Sea sediments Atlantis II - sediments 21°36'19.0" 38°12'09.0 ~3.5 core underlying ATII ATIID-3 SRS1120134 (ATII SDM) N "E length brine pool ATIID-4 SRS1120135 ATIID-5 SRS1120142 ATIID-6 SRS1120143 Discovery Deep brine DDBRINP SRS481325 PRJNA219363 21°17'11.0" 38°17'14.0 2026– Brine pool water N "E 2042 layers (DD INF, DD BR) DDBRINE DD-1 SRS1120158 PRJNA299097 DD-2 SRS1120203 DD-3 SRS1120205 Discovery Deep 2180 + Sea sediments sediments 21°17'11.0" 38°17'14.0 ~3.5 core underlying DD DD-4 SRS1120206 N "E length brine pool (DD SDM) DD-5 SRS1120207 DD-6 SRS1120208 DD-7 SRS1120209 KDBRUINP SRS481335 PRJNA219363 Kebrit Deep brine 24°43'07.3" 36°17'19.7 Brine pool water (KDBRUINP, 1468-1469 KDBRLINP SRS481337 N "E layers KDBRINE, KDBRLINP) KDBRINE SRP150921 PRJNA476873 1856 + BI (NBI) SRS1120214 PRJNA219363 Sea sediments 21°24'31.9" 38°05'37.4 0.37 multi- underlying brine- N "E corer Non-brine sediments influenced site length (NB SDM) 1937 + Sea sediments CD (NBII) SRS1120210 PRJNA219363 21°18'09.3" 38°05'00.2 ~3.5 core underlying brine- N "E length influenced site Guaymas Basin deep- GB VNT SRS289833 PRJNA77837 Guaymas Basin sea hydrothermal deep-sea vent plume water 27°1.852 111°24.000 1775 hydrothermal vent plume water (GB VNT) Kueishantao shallow- G2 (surface water KSW VNT SRS373507 PRJNA178514 sea hydrothermal immediately over vent (water above the vent) water vent) sample from 24°50′N 121°57′E 0 Kueishantao (KSW VNT) shallow-sea hydrothermal system. Kueishantao shallow- G1 (vent) water K VNT SRS373506 PRJNA178514 sea hydrothermal sample from vent (water) Kueishantao 24°50′N 121°57′E 17.2 shallow-sea (K VNT) hydrothermal system. Juan de Fuca Ridge JDF VNT SRS172788 PRJNA47471 Juan de Fuca Ridge hydrothermal vent 129°5.81′ hydrothermal vent diffuse flow seawater 47°57.00′ N 2198 W diffuse flow seawater (JDF VNT) Loki’s Castle deep-sea Biofilm (microbial LC MM SRS745051 PRJNA266758 vent biofilm mat) located on (microbial mat) the midsection of 73°33.97′N 08°09.51′E 2357 the surface of black (LC MM) smoker chimney João, in Loki’s Castle vent field Table S2: The SMGCs detected at each site (absolute values) with the name of the SMGCs detected, the count and total numbers for each site and for each SMGC are denoted. ATII SDM SDM ATII 50 ATII 200 ATII 700 ATII 1500 ATII INF ATII UCL ATII LCL ATII Sites SDM DD NB SDM BR DD INF DD KD BR KD UINF KD LINF GB VNT VNT KSW VNT K VNT JDF MM LC Total Acyl_amino_acids 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 Arylpolyene 0 0 0 5 0 1 0 1 0 0 0 1 0 0 0 0 0 0 0 3 11 Arylpolyene - cf_fatty_acid 1 0 0 1 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 3 Bacteriocin 1 0 0 0 0 0 0 0 0 1 1 3 3 2 6 0 0 1 0 0 18 Cf_fatty_acid 7 2 1 21 29 28 18 0 0 2 10 11 2 22 3 9 3 2 1 11 182 Cf_fatty_acid –Arylpolyene 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 Cf_fatty_acid -Cf_saccharide 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 1 Cf_putative 10 14 3 18 9 31 15 0 0 3 6 45 2 17 6 1 5 5 1 7 198 Cf_saccharide 46 94 10 85 127 205 129 72 94 152 189 449 142 196 309 0 2 1 1 4 2307 Cf_saccharide -Bacteriocin 0 0 0 0 0 0 0 0 0 0 0 0 0 0 3 0 0 0 0 0 3 Cf_saccharide -nrps 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 1 Ectoine 0 0 0 0 0 0 0 0 0 0 0 0 0 2 1 0 0 0 0 0 3 Hserlactone 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 1 Ladderane -Cf_fatty_acid 0 0 0 0 0 0 0 0 0 0 0 0 0 2 0 0 0 0 0 0 2 Lantipeptide 0 0 0 0 0 0 1 0 0 0 0 0 0 1 0 0 0 0 0 0 2 Microcin 0 0 0 1 1 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 3 NRPS 0 0 0 0 0 0 0 0 0 0 1 2 0 3 3 0 0 0 0 0 9 Nrps -T1pks 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 1 Other 0 0 0 0 1 1 1 0 0 2 1 1 0 1 2 0 0 0 0 0 10 OtherKS 0 0 0 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 2 Otherks -Pufa 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 Otherks -Pufa -T1pks 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 1 Otherks -T1pks 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 Phosphonate 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 1 Pufa 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 T1PKS 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 1 T2pks -Cf_fatty_acid 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 1 T3pks 1 0 0 0 0 0 1 0 0 2 2 3 0 0 0 0 0 0 0 0 9 T3pks -cf_saccharide 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 1 Terpene 4 4 2 14 1 0 1 0 0 0 0 5 0 3 0 0 0 1 0 0 35 Thiopeptide 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 1 Total 70 114 16 146 170 269 168 73 94 162 210 524 149 252 334 11 11 10 3 26 2811 Table S3: The normalized number of SMGCs detected at each site (normalized: number of SMGCs detected/ number of assembled reads at each site *10 6), with the name of the SMGCs detected, the count and total numbers for each site and for each SMGC are denoted. In dark blue are the cells with unique SMGCs –only detected once in all the data. Similarly colored cells indicate the SMGCs common to groups of sites (light pink: ATII water column depths, light blue: sediments, yellow: ATII brine layers, bright pink: KD brine layers). ATI ATII KD KS ATII ATII ATII DD NB DD DD ATII ATII ATII KD KD I SD LIN GB W K JDF LC 200 700 1500 SDM SDM BR INF INF UCL LCL BR UINF Sites 50 M F VNT VNT VNT VNT MM Total 0.0 Acyl_amino_acids 0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 1.90 1.90 8.5 Arylpolyene 8 0.00 1.80 0.00 0.00 0.00 0.00 1.31 0.00 0.00 0.00 0.26 0.00 0.00 0.00 0.00 0.00 0.00 0.00 5.71 17.66 Arylpolyene - 1.7 cf_fatty_acid 2 0.00 1.80 0.00 2.09 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 5.61 0.0 Bacteriocin 0 0.00 0.00 0.00 2.09 0.00 0.00 0.00 0.00 1.35 1.26 0.77 3.28 6.48 1.96 0.00 0.00 2.95 0.00 0.00 20.14 36.